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Library Curation for Focused Screening in Drug Discovery
RDKit
Virtual Screening
RDKitVirtual Screening
caizhengguo@dp.tech
发布于 2023-07-30
推荐镜像 :e3nn:0.2
推荐机型 :c8_m16_cpu
赞
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Library Curation for Focused Screening in Drug Discovery
Goals
Table of Contents
1. Data check
2. Feature extraction for the reference library
Descriptor calculation via RDKit
Statistical comparison and visualization
3. Screening library curation
Similarity search: nearest neighbour
Diversity check: clustering by substructures
4. results validation
Property check
Virtual screening for hit check
Summary

Library Curation for Focused Screening in Drug Discovery

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Open In Bohrium

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©️ Copyright 2023 @ Authors
Authorship: Zhengguo Cai 📨
Date: 2023-07-30
Sharing agreement:This work is licensed under 知识共享署名-非商业性使用-相同方式共享 4.0 国际许可协议
Quick start: click Connect button, chose e3nn:0.2 image and any configuration to start.

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High throughput screening (HTS) has become a cornerstone of early-stage drug discovery, allowing rapid testing of large compound libraries against therapeutic targets. However, conventional HTS campaigns suffer from low hit rates, typically under 1%, limiting quality lead compounds to spur drug development. The main reason of having such low hit rates from conventional HTS is the use of a general screening library against the target of interest, whose privileged ligand chemical space might merely overlap with the screening library. Library curation, the strategic design and selection of compound with preferred physiochemical properties, has become a critical tool to improve the effectiveness of HTS. The screening process with curated library is therefore called focused screening. By thoughtfully biasing screening libraries towards chemical matter predicted to be synthetically tractable and biologically active against the target, researchers can achieve much higher hit rates compared to screening against a general library. Key aspects of quality library curation include applying property filters, leveraging structural knowledge of the target, computational modeling of activity, and drawing on accumulated data from past screens. As researchers tackle more challenging drug targets, purposeful curation provides a path to translate screening hits into viable lead compounds with greater efficiency. This notebook will walk through an example of library curation from the field of targeting therapeutic relevant RNAs with small molecules, to demonstrate the overall process of library curation from feature extraction, similarity search and results validation.

Bohrium Notebook (NB) is an open-access platform that allows knowledge run on a free-serving computational node. We welcome readers with different levels of learnings and background knowledge to follow us and practice AI for Science here!

📖 Getting Started Guide
This document can be executed directly on the Bohrium Notebook. To begin, click the Connect button located at the top of the interface, then select the e3nn:0.2 Image and choose your desired machine configuration to proceed.

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Goals

learn how to perform library curation for a target library with a specific reference library

In this tutorial, you will be able to:

  • understand the basic concepts/principles in libaray curation
  • learn the general toolkits in RDKit to characterize a given molecule
  • know the basic methods for chemical feature extraction, similairty search, library comparison and clustering
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Table of Contents

This tutorial takes maximally 20 min for reading plus hand-on practice.

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1. Data check

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[2]
import pandas as pd
from scipy.stats import mannwhitneyu
from scipy.spatial.distance import cdist
import matplotlib.pyplot as plt
import seaborn as sns
from matplotlib.patches import FancyArrow
from sklearn.decomposition import PCA
from sklearn.preprocessing import StandardScaler
from sklearn.manifold import TSNE
from mpl_toolkits.mplot3d import Axes3D
import numpy as np
import os,glob,subprocess
from openbabel import openbabel, pybel
import math
import rdkit
from rdkit import DataStructs, Chem
from rdkit.Chem import AllChem
from rdkit.Chem import Draw
from rdkit.ML.Descriptors import MoleculeDescriptors
from rdkit.Chem import Descriptors, rdMolDescriptors, rdFreeSASA, rdmolops
import tqdm
from multiprocessing import Pool

# %matplotlib notebook
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Firstly, we loaded data of the reference library, in this case, we used RNA-targeting Bioactive lIgaNd Database (R-BIND) as the basis of our curation. R-BIND is a continously updated database that records reported small-molecule ligands binding to various RNA targets from literarures. The SMILES (Co) column records the SMILES of the ligand after tauomerizaiton/protonation correction at pH 7.4.

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[2]
# Download data and load it
ref_lib=pd.read_csv('/data/NB_AT/RBIND_SM.csv')
ref_lib.head()
Name CAS System Target RNA Class RNA Subclass RNA Region SMILES (NC) SMILES (Co) MW ... TC VWSA npr1 npr2 PMI1 PMI2 PMI3 Triangle 1 Triangle 2 Shape
0 5FDQD NaN Bacteria Flavin Mononucleotide (FMN) Riboswitch mRNA Riboswitch 5' UTR CC1=C(C)C=C(N(CCC(C)C2=CC=C(F)C=C2)C(C3=N4)=NC... CC(CCN1C2=CC(C)=C(C)C=C2N=C2C(=O)[N-]C(=O)N=C1... 391.43 ... -1 538.32 0.443446 0.791606 2392.503828 4406.037155 5692.326980 2 2b Hybrid
1 Ribocil-B 1825355-55-2 Bacteria Flavin Mononucleotide (FMN) Riboswitch mRNA Riboswitch 5' UTR CNC1=NC=C(CN2CCC[C@@]([H])(C2)C3=NC(C4=CC=CS4)... CNC1=NC=C(C[NH+]2CCC[C@@H](C2)C2=NC(=CC(=O)N2)... 383.49 ... 1 526.74 0.311695 0.825532 1830.005068 7055.381722 8108.759493 1 1d Rod
2 Ribocil-C 1825355-56-3 Bacteria Flavin Mononucleotide (FMN) Riboswitch mRNA Riboswitch 5' UTR [H][C@](C1)(C(N2)=NC(C3=CC=CS3)=CC2=O)CCCN1CC4... O=C1NC(=NC(=C1)C1=CC=CS1)[C@H]1CCCN(CC2=CN(C=N... 419.51 ... 0 549.10 0.340241 0.772061 2259.112967 8167.790462 9571.033742 2 2b Hybrid
3 Roseoflavin 51093-55-1 Bacteria Flavin Mononucleotide (FMN) Riboswitch mRNA Riboswitch 5' UTR CC1=CC2=C(N(C[C@H](O)[C@H](O)[C@H](O)CO)C3=NC(... CN(C)C1=CC2=C(C=C1C)N=C1C(=O)[N-]C(=O)N=C1N2C[... 404.40 ... -1 545.21 0.469786 0.597186 2918.981341 3791.286767 6285.233908 4 4d Disc
4 2,6-Diaminopurine 1904-98-9 Bacteria pbuE (Purine-Sensing) Riboswitch mRNA Riboswitch 5' UTR NC1=C2NC=NC2=NC(N)=N1 NC1=NC(N)=C2NC=NC2=N1 150.15 ... 0 182.02 0.377043 0.624733 267.151069 442.650018 708.542298 4 4d Disc

5 rows × 37 columns

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To demonstrate the specificity of the reference library, namely the unique chemical space occupied by RNA-targeting small molecules, we compared R-BIND with the FDA-approved drugs (whose targets are mostly proteins) on 20 cheminformatic properties. To make a fair comparison, we chose ligands with molecular weights between upper and lower bound of R-BIND ([141,706]) as the restriction.

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[3]
fda=pd.read_csv('/data/NB_AT/FDA_cheminformatics.csv')
fda.head()
Ligand ID Database ID SMILES (NC) SMILES (Co) MW HBA HBD LogP RotB tPSA ... ArRings HetRings SysRings SysRR Fsp3 nStereo ASA relPSA TC VWSA
0 2 DB00014 O=C(NNC(=O)[C@H]1N(C(=O)[C@@H](NC(=O)[C@@H](NC... CC(C)C[C@H](NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@H... 1270.44 17 18 -6.04 33 495.13 ... 4 4 5 1.2 0.51 9 1594.20 0.27 1 1846.27
1 3 DB00035 O=C(NCC(=O)N)[C@@H](NC(=O)[C@H]1N(C(=O)[C@H]2N... NC(=O)CC[C@@H]1NC(=O)[C@H](CC2=CC=CC=C2)NC(=O)... 1070.23 14 14 -7.51 19 437.15 ... 2 2 4 1.0 0.48 7 1169.54 0.30 1 1481.51
2 4 DB00050 Clc1ccc(C[C@@H](NC(=O)[C@H](NC(=O)C)Cc2cc3c(cc... CC(C)C[C@H](NC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@H... 1432.07 17 17 -3.34 38 497.41 ... 5 2 5 1.2 0.43 10 1819.13 0.24 1 2059.70
3 5 DB00091 O=C1N(C)[C@@H]([C@H](O)[C@@H](C/C=C/C)C)C(=O)N... CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N... 1202.63 12 5 2.68 15 278.80 ... 0 1 1 1.0 0.79 12 1422.47 0.14 0 2033.47
4 6 DB00093 O=C(NCC(=O)N)[C@@H](NC(=O)[C@H]1N(C(=O)[C@H]2N... NC(=O)CC[C@@H]1NC(=O)[C@H](CC2=CC=CC=C2)NC(=O)... 1042.24 11 12 -6.73 19 408.56 ... 2 2 4 1.0 0.50 8 1187.76 0.28 2 1459.31

5 rows × 24 columns

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If we compare these commonly used physicochemical properties of two libraries, we could easily identify that ligands biased RNA bear distiguished properties, such as high N atom count, high aromatic ring count, more total charges and overall more hydrophilic due to the chemical differences between RNA and proteins. It is such differences that encourage us to perform library curation before performing any format of screenings.

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[4]
# Check molecular weight bounds of R-BIND
print(ref_lib['MW'].describe()[['min','max']])
# Box and whisker plots for 20 cheminformatic properties between R-BIND and FDA-approved drugs
# Create subplots
columns=fda.columns[4:24]
fda_sub=fda.loc[(fda['MW'] >= 141) & (fda['MW'] <= 706)]
plt.rcParams['font.size'] = 20
plt.rcParams['axes.linewidth'] = 2
fig, axs = plt.subplots(4, 5, figsize=(40, 30))
axs = axs.flatten()
for i, ax in enumerate(axs):
boxprops = dict(linewidth=4)
whiskerprops = dict(linewidth=4)
medianprops = dict(linewidth=4)
ax.boxplot(ref_lib.iloc[:,i+9],labels=['R-BIND'],positions=[1],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='blue'),medianprops=dict(medianprops,color='blue'))
ax.boxplot(fda.iloc[:,i+4],labels=['FDA'],positions=[2],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='orange'),medianprops=dict(medianprops,color='orange'))
_, p = mannwhitneyu(ref_lib.iloc[:,i+9], fda.iloc[:,i+4])
plot_height = ax.get_yticks()[-1]
if p < 0.05:
ax.axline((1.1, plot_height*0.8), (1.9, plot_height*0.8),color='black', linewidth=5)
ax.text(1.5, plot_height*.7, "*", fontsize=40)
elif p<0.001:
# ax.add_patch(FancyArrow(1.25, plot_height*0.8, 0.5, 0, width=0.01, facecolor='black'))
ax.text(1.5, plot_height*.7, "**", fontsize=40)
ax.set_title(f'{columns[i]}',fontsize=30)
ax.tick_params(labelsize=20)
ax.spines['left'].set_linewidth(3)
ax.spines['bottom'].set_linewidth(3)
ax.spines['top'].set_linewidth(3)
ax.spines['right'].set_linewidth(3)
min    141.13
max    705.93
Name: MW, dtype: float64
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2. Feature extraction for the reference library

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In this part, we will need to calculate the features of our reference library and for a given working library. The working library usually contains a large number of molecules but not all of them are quite related to the chemical space we want to biased towards. Here we use the enamine library, a commercially available library with 15 k molecules representing validated drug-like chemical space.

To be consistent, we used RDKit to calculate desired molecular descriptors for both R-BIND and Chemdiv ligands and make comparison with them.

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Descriptor calculation via RDKit

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The descriptors being calculated by RDKit include molecular weigth, HBA, HBD, LogP, number of rotable bonds, TPSA, ring count, number of aromatic rings, number of aromatic heterocycles, number of aliphatic heterocycles, fraction of sp3 carbons, N count, O count, formal charge and solvent-accessible surface area (SASA).

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def MolsToDescriptors(mol):
"""
Calculate descriptors for a RDKit molecule.

Parameters:
molecule (rdkit.Chem.rdchem.Mol) - RDKit molecule

Returns:
list of float - Values of the descriptors
"""
calc = MoleculeDescriptors.MolecularDescriptorCalculator(['MolWt','NumHAcceptors','NumHDonors','MolLogP',
'NumRotatableBonds', 'TPSA','RingCount',
'NumAromaticRings','NumAromaticHeterocycles',
'NumAliphaticHeterocycles','FractionCSP3'] )
# Add hydrogens and calculate properties
try:
mol = Chem.AddHs(mol)
descriptors = calc.CalcDescriptors(mol)
fc = rdmolops.GetFormalCharge(mol)
atom_list = []
for atom in mol.GetAtoms():
atom_list.append(atom.GetSymbol())
NCount=atom_list.count('N')
OCount=atom_list.count('O')

# Generate 3D conformation for SASA calculation and prepare radii
AllChem.EmbedMolecule(mol)
radii = rdFreeSASA.classifyAtoms(mol)
SASA = rdFreeSASA.CalcSASA(mol, radii)
except:
SASA=0
fc=0
try:
arr=np.array(descriptors)
arr=np.append(arr,[fc,NCount,OCount,SASA])
except:
arr=np.zeros(15,dtype=np.float)
return arr

def SmilesToDescriptors(inputdir,batch_size,outdir,ncores,SMILES='smiles',filename=''):
"""
Calculate descriptors for a list of SMILES strings.

Parameters:
SMILES (str) - SMILES column name of input data
batch_size (int) - Size of batch for parallel processing
ncores (int) - Number of cores to use for parallel processing
inputdir (str) - Path to input csv file with SMILES column
outdir (str) - Path to output directory
filename (str)- prefix of the out .csv file

Returns:
pandas DataFrame with smiles and descriptors
"""
data=pd.read_csv(inputdir)
smiles=data[SMILES]
pool = Pool(processes=ncores)
print(f'Batch processing by batch_size={batch_size}')
print('Number of total batches: ',math.ceil(len(smiles)/batch_size))
for id in range(math.ceil(len(smiles)/batch_size)):
if os.path.exists(outdir+f'{id}_{os.path.basename(inputdir)[:-4]}_para.csv'):
print(outdir+f'{id}_{os.path.basename(inputdir)[:-4]}_para.csv'+ f' exists, process next one: {id+1}')
else:
Out=[]
if id+1 != math.ceil(len(smiles)/batch_size):
print(f'Processing the #{id+1} batch now:')
mols = [Chem.MolFromSmiles(i) for i in tqdm.tqdm(smiles[id*batch_size:(id+1)*batch_size])]
smiles_l=[s for s in smiles[id*batch_size:(id+1)*batch_size]]
print(f'Now calculating descriptors for batch #{id+1}:')
for out in tqdm.tqdm(pool.imap(MolsToDescriptors,mols)):
Out.append(out)
elif id+1 == math.ceil(len(smiles)/batch_size):
print('Processing the last batch now:')
mols = [Chem.MolFromSmiles(i) for i in tqdm.tqdm(smiles[id*batch_size:])]
smiles_l=[s for s in smiles[id*batch_size:]]
print('Now calculating descriptors for last batch')
for out in tqdm.tqdm(pool.imap(MolsToDescriptors,mols)):
Out.append(out)
df_smiles=pd.DataFrame(smiles_l,columns=['smiles'])
df_para=pd.DataFrame(Out,columns=['MW','HBA','HBD','LogP',
'RotB', 'tPSA','Rings',
'ArRings','NumAromaticHeterocycles',
'NumAliphaticHeterocycles','Fsp3','TC','N','O','ASA'])
df_final=pd.concat([df_smiles,df_para],axis=1)
df_final.to_csv(outdir+f'{id}_{os.path.basename(inputdir)[:-4]}_para.csv',index=None)

path=outdir+f'/*{os.path.basename(inputdir)[:-4]}_para.csv'
print(f'Total files being processed: {len(glob.glob(path))}')
dfs=[]
for csvfile in tqdm.tqdm(glob.glob(path)):
df=pd.read_csv(csvfile)
dfs.append(df)
combined_df = pd.concat(dfs, ignore_index=True)
combined_df.to_csv(outdir+f'{filename}_combined_data.csv', index=False)
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This part of code will run descriptor calculations for a given .csv file when given its path (inputdir), output path (outdir), and split the whole dataset into chunks with each of batch_size in size, ncores specify the number of cores being used for calculation, set it as the max cores of your node to speed up the calculation, SMILES specify the SMILES column name of your input data, for instances, "SMILES (Co)" for R-BIND, "ROMol" for enamine, filename specify the prefix of the out .csv file. Each chunk of splitted data will give a .csv result file, and in the end a combined .csv will be generated.

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[31]
# r-bind calculation
SmilesToDescriptors(inputdir='/data/NB_AT/RBIND_SM.csv',outdir='/data/NB_AT/',batch_size=50000,ncores=12,SMILES='SMILES (Co)',filename='rbind')
# enamine calculation
SmilesToDescriptors(inputdir='/data/NB_AT/enamine.csv',outdir='/data/NB_AT/',batch_size=50000,ncores=12,SMILES='ROMol',filename='enamine')
Batch processing by batch_size=50000
Number of total batches:  1
Processing the last batch now:
100%|██████████| 15520/15520 [00:06<00:00, 2442.83it/s]
Now calculating descriptors for last batch
319it [00:06, 46.88it/s][16:20:51] UFFTYPER: Unrecognized atom type: Se2+2 (5)
[16:20:51] UFFTYPER: Unrecognized atom type: Se2+2 (5)
15520it [02:42, 95.79it/s] 
Total files being processed: 1
100%|██████████| 1/1 [00:00<00:00, 22.45it/s]
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[35]
# chemdiv calculation
SmilesToDescriptors(inputdir='/data/NB_AT/chemdiv.csv',outdir='/data/NB_AT/',batch_size=50000,ncores=12,SMILES='smiles',filename='chemdiv')
Batch processing by batch_size=50000
Number of total batches:  1
Processing the last batch now:
100%|██████████| 50000/50000 [00:16<00:00, 3056.56it/s]
Now calculating descriptors for last batch
8868it [02:20, 59.17it/s] [16:46:47] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

18009it [04:48, 59.93it/s] [16:49:14] UFFTYPER: Unrecognized charge state for atom: 14
23409it [06:21, 62.19it/s] [16:51:12] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

26411it [06:59, 52.88it/s][16:51:25] UFFTYPER: Unrecognized atom type: Se2+2 (5)
27913it [07:23, 50.21it/s][16:51:50] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

30678it [08:00, 39.02it/s] [16:52:33] UFFTYPER: Unrecognized atom type: Se2+2 (20)
[16:52:33] UFFTYPER: Unrecognized atom type: Se2+2 (20)
30678it [08:11, 39.02it/s][16:53:30] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

35377it [09:25, 77.92it/s][16:53:54] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

38746it [10:18, 123.52it/s][16:54:43] UFFTYPER: Unrecognized charge state for atom: 17
39119it [10:22, 128.92it/s][16:54:47] UFFTYPER: Unrecognized charge state for atom: 22
42673it [11:15, 44.92it/s] [16:55:39] UFFTYPER: Unrecognized charge state for atom: 11
46481it [12:31, 65.12it/s] [16:57:06] 

****
Pre-condition Violation
No conformers in molecule
Violation occurred on line 134 in file /project/build/temp.linux-x86_64-cpython-38/rdkit/External/FreeSASA/RDFreeSASA.cpp
Failed Expression: mol.getNumConformers()
****

50000it [13:15, 62.88it/s]
Total files being processed: 1
100%|██████████| 1/1 [00:00<00:00,  8.27it/s]
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Statistical comparison and visualization

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Now we can compare the difference between the reference library and working library either property-by-property or a reduced space.

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[6]
# load data
rbind_para = pd.read_csv('/data/NB_AT/rbind_combined_data.csv')
# enamine_para = pd.read_csv('/data/NB_AT/enamine_combined_data.csv')
chemdiv_para = pd.read_csv('/data/NB_AT/chemdiv_combined_data.csv')

# Select 15 features to compare
features = rbind_para.columns[1:]
rbind_para = rbind_para[features]
# enamine_para = enamine_para[features]
chemdiv_para = chemdiv_para[features]

# Plot density plots
fig, axs = plt.subplots(3, 5, figsize=(30, 20))
for i, feature in enumerate(features):
row = i // 5
col = i % 5
ax = axs[row, col]
sns.kdeplot(rbind_para[feature], ax=ax, label='R-BIND')
# sns.kdeplot(enamine_para[feature], ax=ax, label='Enamine')
sns.kdeplot(chemdiv_para[feature], ax=ax, label='Chemdiv')
ax.set_title(feature)
ax.legend()

plt.tight_layout()
plt.show()
ax.legend(loc='upper right')
plt.show()
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[7]
# Box and whisker plots for 15 cheminformatic properties between R-BIND and Chemdiv
# Create subplots
rbind_para = pd.read_csv('/data/NB_AT/rbind_combined_data.csv')
chemdiv_para = pd.read_csv('/data/NB_AT/chemdiv_combined_data.csv')
columns=rbind_para.columns[1:]
# set the same MW threshold as the rbind molecules, though it turns out all the chemdiv molecules are within this range
chemdiv_para=chemdiv_para.loc[(chemdiv_para['MW'] >= 141) & (chemdiv_para['MW'] <= 706)]
plt.rcParams['font.size'] = 20
plt.rcParams['axes.linewidth'] = 2
fig, axs = plt.subplots(3, 5, figsize=(40, 30))
axs = axs.flatten()
for i, ax in enumerate(axs):
boxprops = dict(linewidth=4)
whiskerprops = dict(linewidth=4)
medianprops = dict(linewidth=4)
ax.boxplot(rbind_para.iloc[:,i+1],labels=['R-BIND'],positions=[1],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='blue'),medianprops=dict(medianprops,color='blue'))
ax.boxplot(chemdiv_para.iloc[:,i+1],labels=['Chemidiv'],positions=[2],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='orange'),medianprops=dict(medianprops,color='orange'))
_, p = mannwhitneyu(rbind_para.iloc[:,i+1], chemdiv_para.iloc[:,i+1])
plot_height = ax.get_yticks()[-1]
if p < 0.05:
ax.add_patch(FancyArrow(1.25, plot_height*0.8, 0.5, 0, width=0.01, facecolor='black'))
ax.text(1.5, plot_height*.7, "*", fontsize=40)
elif p<0.001:
ax.add_patch(FancyArrow(1.25, plot_height*.8, 0.5, 0, width=0.01, facecolor='black'))
ax.text(1.5, plot_height*.7, "**", fontsize=40)
ax.set_title(f'{columns[i]}',fontsize=30)
ax.tick_params(labelsize=20)
ax.spines['left'].set_linewidth(3)
ax.spines['bottom'].set_linewidth(3)
ax.spines['top'].set_linewidth(3)
ax.spines['right'].set_linewidth(3)
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We can also use Principle Component Analysis (PCA) to reduce the dimensionality to visualize the distribution of the chemical space of two libraries.

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[8]
# Standardize features
scaler = StandardScaler()
chemdiv_para[features] = scaler.fit_transform(chemdiv_para[features])
rbind_para[features] = scaler.transform(rbind_para[features])

# Apply PCA on rbind_para
pca = PCA(n_components=3)
pca.fit(rbind_para[features])

# Transform datasets
pca_rbind = pca.transform(rbind_para[features])
pca_chemdiv = pca.transform(chemdiv_para[features])

# Plot result
fig = plt.figure(figsize=(10, 10))
ax = fig.add_subplot(111, projection='3d')
ax.view_init(elev=30, azim=20)
ax.scatter(pca_chemdiv[:,0], pca_chemdiv[:,1], pca_chemdiv[:,2], alpha=0.1, label='Chemdiv')
ax.scatter(pca_rbind[:,0], pca_rbind[:,1], pca_rbind[:,2], alpha=1, label='R-BIND',color='red')

ax.set_xlabel('PC 1')
ax.set_ylabel('PC 2')
ax.set_zlabel('PC 3')
ax.legend()
plt.show()
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Since RNA-targeting small molecules usually contains scaffolds with N-containing heretoaromatic rings, the comparison of the substructure from two libraries would be another useful perspective to check the discrepancy. Here we use Morgan fingerprints as the representation of molecular substructures.

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[5]
# load the data that contains SMILES
rbind_para = pd.read_csv('/data/NB_AT/rbind_combined_data.csv')
chemdiv_para = pd.read_csv('/data/NB_AT/chemdiv_combined_data.csv')

# Generate Morgan fingerprints
fp_chemdiv = [AllChem.GetMorganFingerprintAsBitVect(Chem.MolFromSmiles(x),3) for x in chemdiv_para['smiles']]
fp_rbind = [AllChem.GetMorganFingerprintAsBitVect(Chem.MolFromSmiles(x),3) for x in rbind_para['smiles']]

# Convert to pandas dataframe
fp_df1 = pd.DataFrame.from_records(fp_rbind)
fp_df2 = pd.DataFrame.from_records(fp_chemdiv)

# Apply PCA and transform data
pca = PCA(n_components=3)
pca.fit(fp_df1)
pca_fp1 = pca.transform(fp_df1)
pca_fp2 = pca.transform(fp_df2)
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[10]
# Plot result
fig = plt.figure(figsize=(10, 10))
ax = fig.add_subplot(111, projection='3d')
ax.view_init(elev=30, azim=20)
ax.scatter(pca_fp1[:,0], pca_fp1[:,1], pca_fp1[:,2], alpha=1, label='R-BIND',color='red')
ax.scatter(pca_fp2[:,0], pca_fp2[:,1], pca_fp2[:,2], alpha=0.1, label='Chemdiv')

ax.set_xlabel('PC 1')
ax.set_ylabel('PC 2')
ax.set_zlabel('PC 3')

ax.legend()
plt.subplots_adjust(left=0, bottom=0, right=1, top=1)
ax.dist = 12
# plt.show()
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3. Screening library curation

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There are many ways to select the potential ligands from the working library, here we introduce a commonly used similarity search method: nearest neighbour (NN) search. The first step of NN search is to calculate the nearest neighbour distance, which defined as the averaged minimum distance of all ligands in the library. The minimum distance of a ligand in the library is calculated by finding the min distance of the ligand against the rest of the ligands in the library in the normalized chemical space.

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Similarity search: nearest neighbour

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[8]
# We used the 15 cheminformatic properties as the chemical space as the basis of the library curation.
# While since the chemdiv lib did not contained corrected SMILES, the TC of the chemdiv molecules are meaningless. So we ignore that column for analysis.
rbind_para = pd.read_csv('/data/NB_AT/rbind_combined_data.csv')
chemdiv_para = pd.read_csv('/data/NB_AT/chemdiv_combined_data.csv')
scaler = StandardScaler()
features= rbind_para.columns[1:].drop('TC')
rbind_para[features] = scaler.fit_transform(rbind_para[features])
chemdiv_para[features] = scaler.transform(chemdiv_para[features])
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[9]
# Calculate pairwise distance matrix
dist_mat = cdist(rbind_para[features], rbind_para[features])
# Initialize output array
min_dists = np.zeros(len(rbind_para[features]))
# Fill with minimum distance for each row
for i in range(len(rbind_para[features])):
min_dists[i] = dist_mat[i][dist_mat[i]!=0].min()
# Add to dataframe
rbind_para['NN_dist'] = min_dists
NN_dist= rbind_para['NN_dist'].mean()
print(f'The nearest neighbour distance of R-BIND (ref lib) is: {NN_dist}')
The nearest neighbour distance of R-BIND (ref lib) is: 1.2583659043271689
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Then we need to find the molecules in the working library, namely the chemdiv library, that locate within the chemical space occupied by the R-BIND molecules. The chemical space of the R-BIND is defined by the universe of the summed area centered by R-BIND molecules with NN_dist as the radius.

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[10]
# Calculate pairwise distance matrix
dist_mat_comp = cdist(chemdiv_para[features], rbind_para[features])
# Calculate row mins
row_mins = np.min(dist_mat_comp, axis=1, keepdims=True)
# Add as new column
chemdiv_para['min_dist_vs_rbind'] = row_mins
chemdiv_select=chemdiv_para[chemdiv_para['min_dist_vs_rbind']<=NN_dist]
chemdiv_select.reset_index(inplace=True,drop=True)
chemdiv_select.head()
smiles MW HBA HBD LogP RotB tPSA Rings ArRings NumAromaticHeterocycles NumAliphaticHeterocycles Fsp3 TC N O ASA min_dist_vs_rbind
0 O=C(COc1ccccc1)N1CCC(C2c3[nH]cnc3CCN2Cc2ccccc2... 0.208222 -0.285346 -0.828974 0.794727 -0.449405 -0.654861 0.735132 -0.114977 -0.479093 1.645658 0.548307 0.0 -0.375605 0.028556 0.353090 1.109387
1 O=C(NC1CCCN(c2cc(-c3ccncc3)n[nH]2)C1)c1ccsc1 -0.417273 0.089613 -0.423414 0.480096 -0.858892 -0.457865 0.031000 -0.114977 1.272076 0.381602 -0.023147 0.0 -0.052788 -0.539004 -0.536667 1.166294
2 CCCCNC(=O)N1CCn2cccc2C1c1cccc(Oc2ccccc2)c1 -0.124828 -0.660304 -0.828974 1.275939 -0.244662 -0.891572 0.031000 -0.114977 -0.479093 0.381602 0.051142 0.0 -0.698423 0.028556 0.143161 1.168331
3 Cc1n[nH]c(C)c1CNC(=O)CCc1nc(C2CCCN2C(=O)c2cccc... 0.142809 0.464571 -0.423414 0.375948 0.164825 0.224105 0.031000 -0.114977 0.396491 0.381602 0.679221 0.0 0.270030 0.596117 0.318381 0.985592
4 Cc1ccc(NC(=O)CCn2nc(C(=O)N3CCc4ccccc43)ccc2=O)... 0.094068 0.089613 -0.828974 0.536305 -0.244662 -0.293464 0.031000 -0.114977 -0.479093 0.381602 -0.171724 0.0 -0.375605 0.596117 0.173783 1.083781
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So after NN search, original 50k chemdiv library was left with 7.6k molecules. We can now check the distribution of the new molecules versus the R-BIND library.

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[15]
# Apply PCA on rbind_para
pca = PCA(n_components=3)
pca.fit(rbind_para[features])

# Transform datasets
pca_rbind = pca.transform(rbind_para[features])
pca_chemdiv = pca.transform(chemdiv_select[features])

# Plot result
fig = plt.figure(figsize=(10, 10))
ax = fig.add_subplot(111, projection='3d')
ax.view_init(elev=30, azim=20)
ax.scatter(pca_chemdiv[:,0], pca_chemdiv[:,1], pca_chemdiv[:,2], alpha=0.1, label='Chemdiv')
ax.scatter(pca_rbind[:,0], pca_rbind[:,1], pca_rbind[:,2], alpha=1, label='R-BIND',color='red')

ax.set_xlabel('PC 1')
ax.set_ylabel('PC 2')
ax.set_zlabel('PC 3')
ax.legend()
plt.show()
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Diversity check: clustering by substructures

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[17]
# Generate Morgan fingerprints
fp_chemdiv_select = [AllChem.GetMorganFingerprintAsBitVect(Chem.MolFromSmiles(x),3) for x in chemdiv_select['smiles']]
fp_rbind = [AllChem.GetMorganFingerprintAsBitVect(Chem.MolFromSmiles(x),3) for x in rbind_para['smiles']]

# Convert to pandas dataframe
fp_df1 = pd.DataFrame.from_records(fp_rbind)
fp_df2 = pd.DataFrame.from_records(fp_chemdiv_select)
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[ ]
# Create labels
y1 = np.zeros(len(fp_df1))
y2 = np.ones(len(fp_df2))
y = np.concatenate((y1, y2))

# Concatenate data
X = np.concatenate((fp_df1, fp_df2))

# TSNE
tsne = TSNE(n_components=2, random_state=0)
proj = tsne.fit_transform(X)
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[23]
# Plot
# Split projected data
proj1 = proj[:len(fp_df1)]
proj2 = proj[len(fp_df1):]

# Plot datasets separately
plt.scatter(proj1[:,0], proj1[:,1], alpha=1, c='red',label='R-BIND')
plt.scatter(proj2[:,0], proj2[:,1], alpha=0.1, label='Chemdiv_select')

plt.legend()
plt.title('t-SNE plot')
plt.show()
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4. results validation

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Property check

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We can now re-check the cheminformatic properties of selected Chemdiv molecules with R-BIND molecules.

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[11]
# find the de-normalized cheminformatic properties of selected Chemdiv molecules by searching on SMILES
rbind_para = pd.read_csv('/data/NB_AT/rbind_combined_data.csv')
chemdiv_para = pd.read_csv('/data/NB_AT/chemdiv_combined_data.csv')
chemdiv_select_para = chemdiv_para[features][chemdiv_para['smiles'].isin([smiles for smiles in chemdiv_select['smiles']])]
chemdiv_select_para.reset_index(inplace=True,drop=True)
chemdiv_select_para.head()
MW HBA HBD LogP RotB tPSA Rings ArRings NumAromaticHeterocycles NumAliphaticHeterocycles Fsp3 N O ASA
0 430.552 4.0 1.0 3.82670 6.0 61.46 5.0 3.0 1.0 2.0 0.384615 4.0 2.0 538.918297
1 353.451 5.0 2.0 2.93200 4.0 73.91 4.0 3.0 3.0 1.0 0.277778 5.0 1.0 400.550608
2 389.499 3.0 1.0 5.19510 7.0 46.50 4.0 3.0 1.0 1.0 0.291667 3.0 2.0 506.271840
3 422.489 6.0 2.0 2.63584 9.0 117.01 4.0 3.0 2.0 1.0 0.409091 6.0 3.0 533.520698
4 416.481 5.0 1.0 3.09184 7.0 84.30 4.0 3.0 1.0 1.0 0.250000 4.0 3.0 511.033932
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[12]
# Boxplot for comparison
plt.rcParams['font.size'] = 20
plt.rcParams['axes.linewidth'] = 2
fig, axs = plt.subplots(3, 5, figsize=(40, 30))
axs = axs.flatten()
for i, ax in enumerate(axs):
try:
boxprops = dict(linewidth=4)
whiskerprops = dict(linewidth=4)
medianprops = dict(linewidth=4)
ax.boxplot(rbind_para[features].iloc[:,i],labels=['R-BIND'],positions=[1],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='blue'),medianprops=dict(medianprops,color='blue'))
ax.boxplot(chemdiv_select_para.iloc[:,i],labels=['Chemidiv_select'],positions=[2],showfliers=False,whiskerprops=whiskerprops,boxprops=dict(boxprops,color='orange'),medianprops=dict(medianprops,color='orange'))
_, p = mannwhitneyu(rbind_para[features].iloc[:,i], chemdiv_select_para.iloc[:,i])
plot_height = ax.get_yticks()[-1]
if p < 0.05:
ax.add_patch(FancyArrow(1.25, plot_height*0.8, 0.5, 0, width=0.01, facecolor='black'))
ax.text(1.5, plot_height*.7, "*", fontsize=40)
elif p<0.001:
ax.add_patch(FancyArrow(1.25, plot_height*.8, 0.5, 0, width=0.01, facecolor='black'))
ax.text(1.5, plot_height*.7, "**", fontsize=40)
ax.set_title(f'{features[i]}',fontsize=30)
ax.tick_params(labelsize=20)
ax.spines['left'].set_linewidth(3)
ax.spines['bottom'].set_linewidth(3)
ax.spines['top'].set_linewidth(3)
ax.spines['right'].set_linewidth(3)
except:
continue
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Virtual screening for hit check

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Now we could set up a virtual screening to test the different scores before/after library curation. For these molecules, we deployed a RNA target for screening test, using rDock since this is a well-validated docking program for RNA-based docking.

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Based on the installation doc, we need to install the needed packages first: https://rdock.sourceforge.net/installation/

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[33]
os.system('sudo apt update')
os.system('sudo apt install libpopt-dev')
os.system('sudo apt install libpopt0')
sh: 0: getcwd() failed: No such file or directory

WARNING: apt does not have a stable CLI interface. Use with caution in scripts.

Hit:1 http://archive.ubuntu.com/ubuntu focal InRelease
Hit:2 http://archive.ubuntu.com/ubuntu focal-updates InRelease
Get:3 http://archive.ubuntu.com/ubuntu focal-backports InRelease [108 kB]
Get:5 http://security.ubuntu.com/ubuntu focal-security InRelease [114 kB]
Hit:4 https://packagecloud.io/github/git-lfs/ubuntu focal InRelease
Hit:6 https://developer.download.nvidia.cn/compute/cuda/repos/ubuntu2004/x86_64  InRelease
Fetched 222 kB in 13s (17.3 kB/s)
Reading package lists...
Building dependency tree...
Reading state information...
150 packages can be upgraded. Run 'apt list --upgradable' to see them.

0
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[39]
# get the repo and install the rDock
os.system('git clone https://github.com/CBDD/rDock')
os.chdir('/data/NB_AT/rDock')
os.system('make -j 12')
Cloning into 'rDock'...
Updating files: 100% (931/931), done.
make lib
make bin/rbdock bin/rbcavity bin/rbmoegrid bin/rblist bin/rbcalcgrid
make[1]: Entering directory '/data/NB_AT/rDock'
make[1]: Entering directory '/data/NB_AT/rDock'
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/Rbt.o src/lib/Rbt.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/Rbt.o src/lib/Rbt.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAlignTransform.o src/lib/RbtAlignTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAlignTransform.o src/lib/RbtAlignTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAnnotation.o src/lib/RbtAnnotation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAnnotation.o src/lib/RbtAnnotation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAnnotationHandler.o src/lib/RbtAnnotationHandler.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAnnotationHandler.o src/lib/RbtAnnotationHandler.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAromIdxSF.o src/lib/RbtAromIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAromIdxSF.o src/lib/RbtAromIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAtom.o src/lib/RbtAtom.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAtomFuncs.o src/lib/RbtAtomFuncs.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtAtom.o src/lib/RbtAtom.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseBiMolTransform.o src/lib/RbtBaseBiMolTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseFileSink.o src/lib/RbtBaseFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseBiMolTransform.o src/lib/RbtBaseBiMolTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseFileSource.o src/lib/RbtBaseFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseGrid.o src/lib/RbtBaseGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseIdxSF.o src/lib/RbtBaseIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseFileSource.o src/lib/RbtBaseFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseInterSF.o src/lib/RbtBaseInterSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseIntraSF.o src/lib/RbtBaseIntraSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseMolecularFileSink.o src/lib/RbtBaseMolecularFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseMolecularFileSource.o src/lib/RbtBaseMolecularFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseObject.o src/lib/RbtBaseObject.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseSF.o src/lib/RbtBaseSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseTransform.o src/lib/RbtBaseTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseUniMolTransform.o src/lib/RbtBaseUniMolTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBaseInterSF.o src/lib/RbtBaseInterSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBiMolWorkSpace.o src/lib/RbtBiMolWorkSpace.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBond.o src/lib/RbtBond.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCavityFillSF.o src/lib/RbtCavityFillSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCavityGridSF.o src/lib/RbtCavityGridSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCellTokenIter.o src/lib/RbtCellTokenIter.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCharmmDataSource.o src/lib/RbtCharmmDataSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCharmmTypesFileSource.o src/lib/RbtCharmmTypesFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtBiMolWorkSpace.o src/lib/RbtBiMolWorkSpace.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChrom.o src/lib/RbtChrom.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromDihedralElement.o src/lib/RbtChromDihedralElement.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromDihedralRefData.o src/lib/RbtChromDihedralRefData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromElement.o src/lib/RbtChromElement.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChrom.o src/lib/RbtChrom.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromFactory.o src/lib/RbtChromFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromFactory.o src/lib/RbtChromFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromOccupancyElement.o src/lib/RbtChromOccupancyElement.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromOccupancyElement.o src/lib/RbtChromOccupancyElement.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromOccupancyRefData.o src/lib/RbtChromOccupancyRefData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromPositionElement.o src/lib/RbtChromPositionElement.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromPositionRefData.o src/lib/RbtChromPositionRefData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromOccupancyRefData.o src/lib/RbtChromOccupancyRefData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtConstSF.o src/lib/RbtConstSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtConstraint.o src/lib/RbtConstraint.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtContext.o src/lib/RbtContext.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtChromPositionRefData.o src/lib/RbtChromPositionRefData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCrdFileSink.o src/lib/RbtCrdFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCrdFileSink.o src/lib/RbtCrdFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCrdFileSource.o src/lib/RbtCrdFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtCrdFileSource.o src/lib/RbtCrdFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDebug.o src/lib/RbtDebug.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDebug.o src/lib/RbtDebug.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDihedralIntraSF.o src/lib/RbtDihedralIntraSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDihedralSF.o src/lib/RbtDihedralSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDihedralIntraSF.o src/lib/RbtDihedralIntraSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDihedralTargetSF.o src/lib/RbtDihedralTargetSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDirectorySource.o src/lib/RbtDirectorySource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDockingSite.o src/lib/RbtDockingSite.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtElementFileSource.o src/lib/RbtElementFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtEuler.o src/lib/RbtEuler.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFFTGrid.o src/lib/RbtFFTGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtDihedralTargetSF.o src/lib/RbtDihedralTargetSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFilter.o src/lib/RbtFilter.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFilterExpression.o src/lib/RbtFilterExpression.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFilterExpressionVisitor.o src/lib/RbtFilterExpressionVisitor.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFlexAtomFactory.o src/lib/RbtFlexAtomFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtFilter.o src/lib/RbtFilter.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtGATransform.o src/lib/RbtGATransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtGenome.o src/lib/RbtGenome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtGATransform.o src/lib/RbtGATransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtInteractionGrid.o src/lib/RbtInteractionGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtLigandFlexData.o src/lib/RbtLigandFlexData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtInteractionGrid.o src/lib/RbtInteractionGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtLigandSiteMapper.o src/lib/RbtLigandSiteMapper.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMOEGrid.o src/lib/RbtMOEGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtLigandSiteMapper.o src/lib/RbtLigandSiteMapper.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMOL2FileSource.o src/lib/RbtMOL2FileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMdlFileSink.o src/lib/RbtMdlFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMdlFileSource.o src/lib/RbtMdlFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMOL2FileSource.o src/lib/RbtMOL2FileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtModel.o src/lib/RbtModel.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtMdlFileSource.o src/lib/RbtMdlFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtModelMutator.o src/lib/RbtModelMutator.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtModelMutator.o src/lib/RbtModelMutator.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNmrRestraintFileSource.o src/lib/RbtNmrRestraintFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNmrRestraintFileSource.o src/lib/RbtNmrRestraintFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNmrSF.o src/lib/RbtNmrSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNmrSF.o src/lib/RbtNmrSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNoeRestraint.o src/lib/RbtNoeRestraint.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNoeRestraint.o src/lib/RbtNoeRestraint.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNonBondedGrid.o src/lib/RbtNonBondedGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNonBondedGrid.o src/lib/RbtNonBondedGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNonBondedHHSGrid.o src/lib/RbtNonBondedHHSGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNullTransform.o src/lib/RbtNullTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtObserver.o src/lib/RbtObserver.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtNonBondedHHSGrid.o src/lib/RbtNonBondedHHSGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMF.o src/lib/RbtPMF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMF.o src/lib/RbtPMF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFDirSource.o src/lib/RbtPMFDirSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFDirSource.o src/lib/RbtPMFDirSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFGridSF.o src/lib/RbtPMFGridSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFIdxSF.o src/lib/RbtPMFIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFGridSF.o src/lib/RbtPMFGridSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPRMFactory.o src/lib/RbtPRMFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPMFIdxSF.o src/lib/RbtPMFIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtParamHandler.o src/lib/RbtParamHandler.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtParameterFileSource.o src/lib/RbtParameterFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtParamHandler.o src/lib/RbtParamHandler.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtParser.o src/lib/RbtParser.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPdbFileSource.o src/lib/RbtPdbFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPharmaSF.o src/lib/RbtPharmaSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtParameterFileSource.o src/lib/RbtParameterFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPolarIdxSF.o src/lib/RbtPolarIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPolarIntraSF.o src/lib/RbtPolarIntraSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPolarIdxSF.o src/lib/RbtPolarIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPolarSF.o src/lib/RbtPolarSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPolarSF.o src/lib/RbtPolarSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPopulation.o src/lib/RbtPopulation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPopulation.o src/lib/RbtPopulation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPrincipalAxes.o src/lib/RbtPrincipalAxes.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPseudoAtom.o src/lib/RbtPseudoAtom.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPsfFileSink.o src/lib/RbtPsfFileSink.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPrincipalAxes.o src/lib/RbtPrincipalAxes.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPsfFileSource.o src/lib/RbtPsfFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRand.o src/lib/RbtRand.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRandLigTransform.o src/lib/RbtRandLigTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRandPopTransform.o src/lib/RbtRandPopTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRealGrid.o src/lib/RbtRealGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtPsfFileSource.o src/lib/RbtPsfFileSource.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRealGrid.o src/lib/RbtRealGrid.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtReceptorFlexData.o src/lib/RbtReceptorFlexData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtRotSF.o src/lib/RbtRotSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSAIdxSF.o src/lib/RbtSAIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSATypes.o src/lib/RbtSATypes.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtReceptorFlexData.o src/lib/RbtReceptorFlexData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSFAgg.o src/lib/RbtSFAgg.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSFAgg.o src/lib/RbtSFAgg.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSFFactory.o src/lib/RbtSFFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSFFactory.o src/lib/RbtSFFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupPMFSF.o src/lib/RbtSetupPMFSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupPMFSF.o src/lib/RbtSetupPMFSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupPolarSF.o src/lib/RbtSetupPolarSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupPolarSF.o src/lib/RbtSetupPolarSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupSASF.o src/lib/RbtSetupSASF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSimAnnTransform.o src/lib/RbtSimAnnTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSimplexTransform.o src/lib/RbtSimplexTransform.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSetupSASF.o src/lib/RbtSetupSASF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSiteMapper.o src/lib/RbtSiteMapper.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSiteMapper.o src/lib/RbtSiteMapper.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSiteMapperFactory.o src/lib/RbtSiteMapperFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSolventFlexData.o src/lib/RbtSolventFlexData.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSphereSiteMapper.o src/lib/RbtSphereSiteMapper.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtStringTokenIter.o src/lib/RbtStringTokenIter.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSiteMapperFactory.o src/lib/RbtSiteMapperFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSubject.o src/lib/RbtSubject.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTetherSF.o src/lib/RbtTetherSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtSubject.o src/lib/RbtSubject.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtToken.o src/lib/RbtToken.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTransformAgg.o src/lib/RbtTransformAgg.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtToken.o src/lib/RbtToken.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTransformFactory.o src/lib/RbtTransformFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTransformFactory.o src/lib/RbtTransformFactory.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTriposAtomType.o src/lib/RbtTriposAtomType.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwGridSF.o src/lib/RbtVdwGridSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtTriposAtomType.o src/lib/RbtTriposAtomType.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwIdxSF.o src/lib/RbtVdwIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwIntraSF.o src/lib/RbtVdwIntraSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwIdxSF.o src/lib/RbtVdwIdxSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwSF.o src/lib/RbtVdwSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtVdwSF.o src/lib/RbtVdwSF.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtWorkSpace.o src/lib/RbtWorkSpace.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/RbtWorkSpace.o src/lib/RbtWorkSpace.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/simplex/NMSearch.o import/simplex/src/NMSearch.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/simplex/NMSearch.o import/simplex/src/NMSearch.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/simplex/NMSearch.o import/simplex/src/NMSearch.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/simplex/NMSearch.o import/simplex/src/NMSearch.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPChromosome.o src/GP/RbtGPChromosome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPChromosome.o src/GP/RbtGPChromosome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFCHK1.o src/GP/RbtGPFFCHK1.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFCHK1.o src/GP/RbtGPFFCHK1.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFCrossDock.o src/GP/RbtGPFFCrossDock.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFCrossDock.o src/GP/RbtGPFFCrossDock.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPChromosome.o src/GP/RbtGPChromosome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPChromosome.o src/GP/RbtGPChromosome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFGold.o src/GP/RbtGPFFGold.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFGold.o src/GP/RbtGPFFGold.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFHSP90.o src/GP/RbtGPFFHSP90.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFHSP90.o src/GP/RbtGPFFHSP90.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFGold.o src/GP/RbtGPFFGold.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFGold.o src/GP/RbtGPFFGold.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFSpike.o src/GP/RbtGPFFSpike.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFSpike.o src/GP/RbtGPFFSpike.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFitnessFunction.o src/GP/RbtGPFitnessFunction.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFitnessFunction.o src/GP/RbtGPFitnessFunction.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPGenome.o src/GP/RbtGPGenome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPGenome.o src/GP/RbtGPGenome.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPParser.o src/GP/RbtGPParser.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPParser.o src/GP/RbtGPParser.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPPopulation.o src/GP/RbtGPPopulation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPPopulation.o src/GP/RbtGPPopulation.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFSpike.o src/GP/RbtGPFFSpike.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -c -o obj/GP/RbtGPFFSpike.o src/GP/RbtGPFFSpike.cxx
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -shared -L./lib obj/Rbt.o obj/RbtAlignTransform.o obj/RbtAnnotation.o obj/RbtAnnotationHandler.o obj/RbtAromIdxSF.o obj/RbtAtom.o obj/RbtAtomFuncs.o obj/RbtBaseBiMolTransform.o obj/RbtBaseFileSink.o obj/RbtBaseFileSource.o obj/RbtBaseGrid.o obj/RbtBaseIdxSF.o obj/RbtBaseInterSF.o obj/RbtBaseIntraSF.o obj/RbtBaseMolecularFileSink.o obj/RbtBaseMolecularFileSource.o obj/RbtBaseObject.o obj/RbtBaseSF.o obj/RbtBaseTransform.o obj/RbtBaseUniMolTransform.o obj/RbtBiMolWorkSpace.o obj/RbtBond.o obj/RbtCavityFillSF.o obj/RbtCavityGridSF.o obj/RbtCellTokenIter.o obj/RbtCharmmDataSource.o obj/RbtCharmmTypesFileSource.o obj/RbtChrom.o obj/RbtChromDihedralElement.o obj/RbtChromDihedralRefData.o obj/RbtChromElement.o obj/RbtChromFactory.o obj/RbtChromOccupancyElement.o obj/RbtChromOccupancyRefData.o obj/RbtChromPositionElement.o obj/RbtChromPositionRefData.o obj/RbtConstSF.o obj/RbtConstraint.o obj/RbtContext.o obj/RbtCrdFileSink.o obj/RbtCrdFileSource.o obj/RbtDebug.o obj/RbtDihedralIntraSF.o obj/RbtDihedralSF.o obj/RbtDihedralTargetSF.o obj/RbtDirectorySource.o obj/RbtDockingSite.o obj/RbtElementFileSource.o obj/RbtEuler.o obj/RbtFFTGrid.o obj/RbtFilter.o obj/RbtFilterExpression.o obj/RbtFilterExpressionVisitor.o obj/RbtFlexAtomFactory.o obj/RbtGATransform.o obj/RbtGenome.o obj/RbtInteractionGrid.o obj/RbtLigandFlexData.o obj/RbtLigandSiteMapper.o obj/RbtMOEGrid.o obj/RbtMOL2FileSource.o obj/RbtMdlFileSink.o obj/RbtMdlFileSource.o obj/RbtModel.o obj/RbtModelMutator.o obj/RbtNmrRestraintFileSource.o obj/RbtNmrSF.o obj/RbtNoeRestraint.o obj/RbtNonBondedGrid.o obj/RbtNonBondedHHSGrid.o obj/RbtNullTransform.o obj/RbtObserver.o obj/RbtPMF.o obj/RbtPMFDirSource.o obj/RbtPMFGridSF.o obj/RbtPMFIdxSF.o obj/RbtPRMFactory.o obj/RbtParamHandler.o obj/RbtParameterFileSource.o obj/RbtParser.o obj/RbtPdbFileSource.o obj/RbtPharmaSF.o obj/RbtPolarIdxSF.o obj/RbtPolarIntraSF.o obj/RbtPolarSF.o obj/RbtPopulation.o obj/RbtPrincipalAxes.o obj/RbtPseudoAtom.o obj/RbtPsfFileSink.o obj/RbtPsfFileSource.o obj/RbtRand.o obj/RbtRandLigTransform.o obj/RbtRandPopTransform.o obj/RbtRealGrid.o obj/RbtReceptorFlexData.o obj/RbtRotSF.o obj/RbtSAIdxSF.o obj/RbtSATypes.o obj/RbtSFAgg.o obj/RbtSFFactory.o obj/RbtSetupPMFSF.o obj/RbtSetupPolarSF.o obj/RbtSetupSASF.o obj/RbtSimAnnTransform.o obj/RbtSimplexTransform.o obj/RbtSiteMapper.o obj/RbtSiteMapperFactory.o obj/RbtSolventFlexData.o obj/RbtSphereSiteMapper.o obj/RbtStringTokenIter.o obj/RbtSubject.o obj/RbtTetherSF.o obj/RbtToken.o obj/RbtTransformAgg.o obj/RbtTransformFactory.o obj/RbtTriposAtomType.o obj/RbtVdwGridSF.o obj/RbtVdwIdxSF.o obj/RbtVdwIntraSF.o obj/RbtVdwSF.o obj/RbtWorkSpace.o obj/simplex/NMSearch.o obj/GP/RbtGPChromosome.o obj/GP/RbtGPFFCHK1.o obj/GP/RbtGPFFCrossDock.o obj/GP/RbtGPFFGold.o obj/GP/RbtGPFFHSP90.o obj/GP/RbtGPFFSpike.o obj/GP/RbtGPFitnessFunction.o obj/GP/RbtGPGenome.o obj/GP/RbtGPParser.o obj/GP/RbtGPPopulation.o -o lib/libRbt.so -lpopt -lm
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -shared -L./lib obj/Rbt.o obj/RbtAlignTransform.o obj/RbtAnnotation.o obj/RbtAnnotationHandler.o obj/RbtAromIdxSF.o obj/RbtAtom.o obj/RbtAtomFuncs.o obj/RbtBaseBiMolTransform.o obj/RbtBaseFileSink.o obj/RbtBaseFileSource.o obj/RbtBaseGrid.o obj/RbtBaseIdxSF.o obj/RbtBaseInterSF.o obj/RbtBaseIntraSF.o obj/RbtBaseMolecularFileSink.o obj/RbtBaseMolecularFileSource.o obj/RbtBaseObject.o obj/RbtBaseSF.o obj/RbtBaseTransform.o obj/RbtBaseUniMolTransform.o obj/RbtBiMolWorkSpace.o obj/RbtBond.o obj/RbtCavityFillSF.o obj/RbtCavityGridSF.o obj/RbtCellTokenIter.o obj/RbtCharmmDataSource.o obj/RbtCharmmTypesFileSource.o obj/RbtChrom.o obj/RbtChromDihedralElement.o obj/RbtChromDihedralRefData.o obj/RbtChromElement.o obj/RbtChromFactory.o obj/RbtChromOccupancyElement.o obj/RbtChromOccupancyRefData.o obj/RbtChromPositionElement.o obj/RbtChromPositionRefData.o obj/RbtConstSF.o obj/RbtConstraint.o obj/RbtContext.o obj/RbtCrdFileSink.o obj/RbtCrdFileSource.o obj/RbtDebug.o obj/RbtDihedralIntraSF.o obj/RbtDihedralSF.o obj/RbtDihedralTargetSF.o obj/RbtDirectorySource.o obj/RbtDockingSite.o obj/RbtElementFileSource.o obj/RbtEuler.o obj/RbtFFTGrid.o obj/RbtFilter.o obj/RbtFilterExpression.o obj/RbtFilterExpressionVisitor.o obj/RbtFlexAtomFactory.o obj/RbtGATransform.o obj/RbtGenome.o obj/RbtInteractionGrid.o obj/RbtLigandFlexData.o obj/RbtLigandSiteMapper.o obj/RbtMOEGrid.o obj/RbtMOL2FileSource.o obj/RbtMdlFileSink.o obj/RbtMdlFileSource.o obj/RbtModel.o obj/RbtModelMutator.o obj/RbtNmrRestraintFileSource.o obj/RbtNmrSF.o obj/RbtNoeRestraint.o obj/RbtNonBondedGrid.o obj/RbtNonBondedHHSGrid.o obj/RbtNullTransform.o obj/RbtObserver.o obj/RbtPMF.o obj/RbtPMFDirSource.o obj/RbtPMFGridSF.o obj/RbtPMFIdxSF.o obj/RbtPRMFactory.o obj/RbtParamHandler.o obj/RbtParameterFileSource.o obj/RbtParser.o obj/RbtPdbFileSource.o obj/RbtPharmaSF.o obj/RbtPolarIdxSF.o obj/RbtPolarIntraSF.o obj/RbtPolarSF.o obj/RbtPopulation.o obj/RbtPrincipalAxes.o obj/RbtPseudoAtom.o obj/RbtPsfFileSink.o obj/RbtPsfFileSource.o obj/RbtRand.o obj/RbtRandLigTransform.o obj/RbtRandPopTransform.o obj/RbtRealGrid.o obj/RbtReceptorFlexData.o obj/RbtRotSF.o obj/RbtSAIdxSF.o obj/RbtSATypes.o obj/RbtSFAgg.o obj/RbtSFFactory.o obj/RbtSetupPMFSF.o obj/RbtSetupPolarSF.o obj/RbtSetupSASF.o obj/RbtSimAnnTransform.o obj/RbtSimplexTransform.o obj/RbtSiteMapper.o obj/RbtSiteMapperFactory.o obj/RbtSolventFlexData.o obj/RbtSphereSiteMapper.o obj/RbtStringTokenIter.o obj/RbtSubject.o obj/RbtTetherSF.o obj/RbtToken.o obj/RbtTransformAgg.o obj/RbtTransformFactory.o obj/RbtTriposAtomType.o obj/RbtVdwGridSF.o obj/RbtVdwIdxSF.o obj/RbtVdwIntraSF.o obj/RbtVdwSF.o obj/RbtWorkSpace.o obj/simplex/NMSearch.o obj/GP/RbtGPChromosome.o obj/GP/RbtGPFFCHK1.o obj/GP/RbtGPFFCrossDock.o obj/GP/RbtGPFFGold.o obj/GP/RbtGPFFHSP90.o obj/GP/RbtGPFFSpike.o obj/GP/RbtGPFitnessFunction.o obj/GP/RbtGPGenome.o obj/GP/RbtGPParser.o obj/GP/RbtGPPopulation.o -o lib/libRbt.so -lpopt -lm
make[1]: Leaving directory '/data/NB_AT/rDock'
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -L./lib -o bin/rbdock src/exe/rbdock.cxx -lpopt -lm -lRbt
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -L./lib -o bin/rbcavity src/exe/rbcavity.cxx -lpopt -lm -lRbt
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -L./lib -o bin/rbmoegrid src/exe/rbmoegrid.cxx -lpopt -lm -lRbt
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -L./lib -o bin/rblist src/exe/rblist.cxx -lpopt -lm -lRbt
g++ -Werror -pipe -std=c++14 -fPIC -O3 -ffast-math   -D_NDEBUG -I./include/ -I./include/GP -I./import/ -I./import/simplex -I./import/simplex/include -I./import/simplex/src -I./import/tnt -I./import/tnt/include -L./lib -o bin/rbcalcgrid src/exe/rbcalcgrid.cxx -lpopt -lm -lRbt
make[1]: Leaving directory '/data/NB_AT/rDock'

0
代码
文本
[40]
# test the installation if it's successful
os.system('make test')
make lib
make[1]: Entering directory '/data/NB_AT/rDock'
make[1]: Nothing to be done for 'lib'.
make[1]: Leaving directory '/data/NB_AT/rDock'
make bin/rbdock bin/rbcavity bin/rbmoegrid bin/rblist bin/rbcalcgrid
make[1]: Entering directory '/data/NB_AT/rDock'
make[1]: 'bin/rbdock' is up to date.
make[1]: 'bin/rbcavity' is up to date.
make[1]: 'bin/rbmoegrid' is up to date.
make[1]: 'bin/rblist' is up to date.
make[1]: 'bin/rbcalcgrid' is up to date.
make[1]: Leaving directory '/data/NB_AT/rDock'
make test_rbcavity test_dock_run
make[1]: Entering directory '/data/NB_AT/rDock'
cd tests/data ; RBT_ROOT=../.. LD_LIBRARY_PATH=../../lib:/usr/local/cuda/lib64:/usr/local/cuda/lib64: ../../bin/rbcavity -r1koc.prm -was
***********************************************
The rDock program is licensed under GNU-LGPLv3.0. http://rdock.sourceforge.net/
Executable:	rbcavity ($Id: //depot/dev/client3/rdock/2021.1/src/exe/rbcavity.cxx#3 $)
Library:	libRbt.so/2021.1/901 2021/07/19
RBT_ROOT:	../..
RBT_HOME:	/root
Current dir:	/data/NB_AT/rDock/tests/data
Date:		Wed Aug  2 15:48:32 2023
***********************************************

Command line arguments:
-r 1koc.prm
-was

MAPPER
CLASS	RbtLigandSiteMapper
ENABLED	TRUE
GRIDSTEP	0.5
MAX_CAVITIES	1
MIN_VOLUME	100
NAME	MAPPER
RADIUS	4.0
REF_MOL	1koc_c.sd
SMALL_SPHERE	1.0
TRACE	1
VOL_INCR	0.0

Size=4076 points; Vol=509.5 A^3; Min=(-3,-2,26); Max=(9,12,36.5); Center=(4.01607,5.29232,31.2635); Extent=(12,14,10.5)

DOCKING SITE
Total volume 509.5 A^3
Cavity #1	Size=4076 points; Vol=509.5 A^3; Min=(-3,-2,26); Max=(9,12,36.5); Center=(4.01607,5.29232,31.2635); Extent=(12,14,10.5)

Cav = 4076; total = 4076
cd tests/data ; RBT_ROOT=../.. LD_LIBRARY_PATH=../../lib:/usr/local/cuda/lib64:/usr/local/cuda/lib64: ../../bin/rbcavity -r1YET.prm -was
***********************************************
The rDock program is licensed under GNU-LGPLv3.0. http://rdock.sourceforge.net/
Executable:	rbcavity ($Id: //depot/dev/client3/rdock/2021.1/src/exe/rbcavity.cxx#3 $)
Library:	libRbt.so/2021.1/901 2021/07/19
RBT_ROOT:	../..
RBT_HOME:	/root
Current dir:	/data/NB_AT/rDock/tests/data
Date:		Wed Aug  2 15:48:33 2023
***********************************************

Command line arguments:
-r 1YET.prm
-was

MAPPER
CLASS	RbtLigandSiteMapper
ENABLED	TRUE
GRIDSTEP	0.5
MAX_CAVITIES	1
MIN_VOLUME	100
NAME	MAPPER
RADIUS	6.0
REF_MOL	1YET_c.sd
SMALL_SPHERE	1.0
TRACE	1
VOL_INCR	0.0

Size=16487 points; Vol=2060.88 A^3; Min=(24,-3,15.5); Max=(44,16.5,35); Center=(34.7872,6.08871,24.663); Extent=(20,19.5,19.5)

DOCKING SITE
Total volume 2060.88 A^3
Cavity #1	Size=16487 points; Vol=2060.88 A^3; Min=(24,-3,15.5); Max=(44,16.5,35); Center=(34.7872,6.08871,24.663); Extent=(20,19.5,19.5)

Cav = 16487; total = 16487
cd tests/data ; RBT_ROOT=../.. LD_LIBRARY_PATH=../../lib:/usr/local/cuda/lib64:/usr/local/cuda/lib64: ../../bin/rbcavity -r1YET_test.prm -was
***********************************************
The rDock program is licensed under GNU-LGPLv3.0. http://rdock.sourceforge.net/
Executable:	rbcavity ($Id: //depot/dev/client3/rdock/2021.1/src/exe/rbcavity.cxx#3 $)
Library:	libRbt.so/2021.1/901 2021/07/19
RBT_ROOT:	../..
RBT_HOME:	/root
Current dir:	/data/NB_AT/rDock/tests/data
Date:		Wed Aug  2 15:48:45 2023
***********************************************

Command line arguments:
-r 1YET_test.prm
-was

MAPPER
CLASS	RbtLigandSiteMapper
ENABLED	TRUE
GRIDSTEP	0.5
MAX_CAVITIES	1
MIN_VOLUME	100
NAME	MAPPER
RADIUS	6.0
REF_MOL	1YET_c.sd
SMALL_SPHERE	1.0
TRACE	0
VOL_INCR	0.0


DOCKING SITE
Total volume 2060.88 A^3
Cavity #1	Size=16487 points; Vol=2060.88 A^3; Min=(24,-3,15.5); Max=(44,16.5,35); Center=(34.7872,6.08871,24.663); Extent=(20,19.5,19.5)

Cav = 16487; total = 16487
make lib
make[2]: Entering directory '/data/NB_AT/rDock'
make[2]: Nothing to be done for 'lib'.
make[2]: Leaving directory '/data/NB_AT/rDock'
make bin/rbdock bin/rbcavity bin/rbmoegrid bin/rblist bin/rbcalcgrid
make[2]: Entering directory '/data/NB_AT/rDock'
make[2]: 'bin/rbdock' is up to date.
make[2]: 'bin/rbcavity' is up to date.
make[2]: 'bin/rbmoegrid' is up to date.
make[2]: 'bin/rblist' is up to date.
make[2]: 'bin/rbcalcgrid' is up to date.
make[2]: Leaving directory '/data/NB_AT/rDock'
mkdir -p tests/results
cd tests/data ; RBT_ROOT=../.. LD_LIBRARY_PATH=../../lib:/usr/local/cuda/lib64:/usr/local/cuda/lib64: ../../bin/rbdock -r1YET_test.prm -i 1YET_c.sd -p dock.prm -n 1 -s 48151623 -o ../results/1YET_test_out > ../results/1YET_test_out.log
[OK] coordinates match
[OK] - scores match
make[1]: Leaving directory '/data/NB_AT/rDock'

0
代码
文本
[2]
# run a test case
os.chdir('/data/NB_AT/rDock/tests/data')
# Command to run
cmd = ['rbdock', '-i','/data/NB_AT/rDock/tests/data/1koc_c.sd','-o','/data/NB_AT/rDock/tests/results/1koc_test','-r','/data/NB_AT/rDock/tests/data/1koc.prm','-p','/data/NB_AT/rDock/data/scripts/dock_solv.prm','-n','1']
# Environment variables to set
env = {
'PATH': '/data/NB_AT/rDock/bin',
'LD_LIBRARY_PATH': '/data/NB_AT/rDock/lib',
'RBT_ROOT': '/data/NB_AT/rDock'
}
# Run command with env vars
result = subprocess.run(cmd, env=env)
print(result.stdout)
***********************************************
The rDock program is licensed under GNU-LGPLv3.0. http://rdock.sourceforge.net/
Executable:	rbdock ($Id: //depot/dev/client3/rdock/2021.1/src/exe/rbdock.cxx#4 $)
Library:	libRbt.so/2021.1/901 2021/07/19
RBT_ROOT:	/data/NB_AT/rDock
RBT_HOME:	/data/NB_AT/rDock/tests/data
Current dir:	/data/NB_AT/rDock/tests/data
Date:		Thu Aug  3 16:18:25 2023
***********************************************


Command line args:
 -i /data/NB_AT/rDock/tests/data/1koc_c.sd
 -r /data/NB_AT/rDock/tests/data/1koc.prm
 -p /data/NB_AT/rDock/data/scripts/dock_solv.prm
 -o /data/NB_AT/rDock/tests/results/1koc_test
 -n 1
Reading polar hydrogens only from ligand SD file

DOCKING PROTOCOL:
/data/NB_AT/rDock/data/scripts/dock_solv.prm
Free docking (with SOLVATION, indexed VDW)

RECEPTOR:
/data/NB_AT/rDock/tests/data/1koc.prm
RNA APTAMER COMPLEXED WITH ARGININE, NMR

DOCKING SITE
Total volume 509.5 A^3
Cavity #1	Size=4076 points; Vol=509.5 A^3; Min=(-3,-2,26); Max=(9,12,36.5); Center=(4.01607,5.29232,31.2635); Extent=(12,14,10.5)


No solvent

------------- Terminate filter 0------------

if (SCORE.NRUNS - 0 ) > 0 then
	0.0 
else
	-1.0 
end


**************************************************
RECORD #1
NAME:   1koc cryst
RANDOM_NUMBER_SEED:           1691050706

END OF RUN
None
代码
文本
[24]
# now set up the large scale docking using rDock
# first generate ligand .mol2 file
def smiles_to_mol2(smiles, output_file):
# Convert SMILES string to Open Babel molecule
mol = pybel.readstring('smi', smiles)
mol.addh()
mol.make3D()

# Write Open Babel molecule to .mol2 file
mol.write('mol2', output_file)

os.mkdir('/data/NB_AT/rDock/tests/data/chemdiv')
ligand_smiles = [smiles for smiles in chemdiv_para['smiles'][:500]]
i=0
for smiles in tqdm.tqdm(ligand_smiles):
output_file=f'/data/NB_AT/rDock/tests/data/chemdiv/{i}.mol2'
smiles_to_mol2(smiles, output_file)
i+=1
print('Done!')
 12%|█▏        | 62/500 [00:05<00:33, 12.89it/s]==============================
*** Open Babel Warning  in CorrectStereoAtoms
  Could not correct 1 stereocenter(s) in this molecule ()
  with Atom Ids as follows: 1
 74%|███████▍  | 370/500 [00:33<00:12, 10.53it/s]==============================
*** Open Babel Warning  in CorrectStereoAtoms
  Could not correct 2 stereocenter(s) in this molecule ()
  with Atom Ids as follows: 1 11
 84%|████████▎ | 418/500 [00:37<00:06, 12.01it/s]==============================
*** Open Babel Warning  in CorrectStereoAtoms
  Could not correct 1 stereocenter(s) in this molecule ()
  with Atom Ids as follows: 1
100%|██████████| 500/500 [00:45<00:00, 11.04it/s]Done!
代码
文本

Before docking, we need to perform ligand correction, here we used openbabel and specifically, we add Hydrogen, charge (gastaiger) and protonation specific to pH 7.4.

代码
文本
[5]
# save the corrected ligand.mol2 file in a new folder.
os.chdir('/data/NB_AT/rDock/tests/data/chemdiv')
!ls *.mol2 | tee ligand_list.txt
ligand_list = "/data/NB_AT/rDock/tests/data/chemdiv/ligand_list.txt"
!mkdir /data/NB_AT/rDock/tests/data/chemdiv_corrected
os.chdir('/data/NB_AT/rDock/tests/data/chemdiv_corrected')

with open(ligand_list) as f:
ligands = f.readlines()
for ligand in ligands:
cmdline=f'obabel -imol2 /data/NB_AT/rDock/tests/data/chemdiv/{ligand[:-1]} -osdf -b -p 7.4 --ff "gasteiger" -O /data/NB_AT/rDock/tests/data/chemdiv_corrected/{ligand[:-6]}.sdf '
os.system(cmdline)
0.mol2
1.mol2
10.mol2
100.mol2
101.mol2
102.mol2
103.mol2
104.mol2
105.mol2
106.mol2
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代码
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Then we downloaded the RNA file (.mol2 file contains the apo structure of microRNA-21), perform similar correction on the receptor file.

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[8]
cmdline='obabel -imol2 /data/NB_AT/rDock/tests/data/rna/miR21.mol2 -omol2 -b --ff -p 7.4 "gasteiger" -O /data/NB_AT/rDock/tests/data/rna_corrected/miR21.mol2'
os.system(cmdline)
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代码
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Then we set up the rDock and record the lowest binding score from 10 binding poses.

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[3]
def write_file(output_file, outline):
buffer = open(output_file, 'w')
buffer.write(outline)
buffer.close()

def rdock_score(ligand_id):
try:
print('start*************************%s***************************' % ligand_id)
if os.path.exists("/data/NB_AT/rDock/tests/data/chemdiv_corrected/%s.sdf" % (ligand_id)):
if not os.path.exists("/data/NB_AT/rDock/tests/results/NB_AT/%s/cavity_cav1.grd" % (ligand_id)):
outline = '''RBT_PARAMETER_FILE_V1.00
TITLE %s_dock

RECEPTOR_FILE /data/rna_targets/full_length_rna_mol2_files/tau_premrna/6va1.mol2
### RECEPTOR_FLEX 3.0

##################################################################
### CAVITY DEFINITION: REFERENCE LIGAND METHOD
##################################################################
SECTION MAPPER
SITE_MAPPER RbtLigandSiteMapper
REF_MOL /data/NB_AT/rDock/tests/data/chemdiv_corrected/%s.sdf
RADIUS 6.0
SMALL_SPHERE 1.5
## LARGE_SPHERE 6.0
MAX_CAVITIES 1
MIN_VOLUME 100
VOL_INCR 0.0
GRIDSTEP 0.5
END_SECTION

#################################
#CAVITY RESTRAINT PENALTY
#################################
SECTION CAVITY
SCORING_FUNCTION RbtCavityGridSF
WEIGHT 1.0
END_SECTION
''' % (ligand_id,ligand_id)
try:
write_file('/data/NB_AT/rDock/tests/results/NB_AT/%s/cavity.prm' % (ligand_id), outline) # cavity generation, which gives a .as file for rbdock
cmdline = 'cd /data/NB_AT/rDock &&'
# cmdline += 'cp /data/NB_AT/rDock/tests/data/rna/miR21.mol2 /data/NB_AT/rDock/tests/results/NB_AT/%s/miR21.mol2 &&' % (ligand_id)
cmdline += 'rbcavity -was -d -r /data/NB_AT/rDock/tests/results/NB_AT/%s/cavity.prm' % (ligand_id)
os.system(cmdline)
except:
pass

# # docking
# if os.path.exists("/data/NB_AT/rDock/tests/results/NB_AT/%s/cavity_cav1.grd" % (ligand_id)):
# if not os.path.exists("/data/NB_AT/rDock/tests/results/NB_AT/%s/stand.txt" % (ligand_id)):
# try:
# cmdline = 'cd /data/NB_AT/rDock &&'
# cmdline += 'rbdock -i /data/NB_AT/rDock/tests/data/chemdiv_corrected/%s.sdf -o stand -r /data/NB_AT/rDock/tests/results/NB_AT/%s/cavity.prm -p /data/NB_AT/rDock/data/scripts/dock_solv.prm -n 100 &&' % (
# ligand_id,ligand_id)
# cmdline += 'sdreport -l stand.sd > /data/NB_AT/rDock/tests/results/NB_AT/%s/stand.txt ' % (ligand_id)
# os.system(cmdline)
# except:
# pass

# score
if os.path.exists("/data/NB_AT/rDock/tests/results/NB_AT/%s/cavity_cav1.grd" % (ligand_id)):
if not os.path.exists("/data/NB_AT/rDock/tests/results/NB_AT/%s/score.txt" % (ligand_id)):
try:
cmdline = 'cd /data/NB_AT/rDock &&'
cmdline += 'rbdock -i /data/NB_AT/rDock/tests/data/chemdiv_corrected/%s.sdf -o score -r /data/NB_AT/rDock/tests/results/NB_AT/%s/cavity.prm -p /data/NB_AT/rDock/data/scripts/dock.prm -n 1 &&' % (
ligand_id,ligand_id)
cmdline += 'sdreport -l score.sd > /data/NB_AT/rDock/tests/results/NB_AT/%s/score.txt ' % (ligand_id)
os.system(cmdline)
except:
pass
except:
print('Error for %s' % ligand_id)
代码
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[4]
# perform docking
ligand_id_l=[os.path.basename(i).split('.')[0] for i in glob.glob('/data/NB_AT/rDock/tests/data/chemdiv_corrected/*.sdf')]
for ligand_id in ligand_id_l[:10]:
if not os.path.exists(f'/data/NB_AT/rDock/tests/results/NB_AT/{ligand_id}'):
os.mkdir(f'/data/NB_AT/rDock/tests/results/NB_AT/{ligand_id}')
rdock_score(ligand_id)
start*************************0***************************
***********************************************
The rDock program is licensed under GNU-LGPLv3.0. http://rdock.sourceforge.net/
Executable:	rbcavity ($Id: //depot/dev/client3/rdock/2021.1/src/exe/rbcavity.cxx#3 $)
Library:	libRbt.so/2021.1/901 2021/07/19
RBT_ROOT:	/data/NB_AT/rDock
RBT_HOME:	/root
Current dir:	/data/NB_AT/rDock
Date:		Mon Aug  7 10:55:28 2023
***********************************************

Command line arguments:
-r /data/NB_AT/rDock/tests/results/NB_AT/0/cavity.prm
-was
-d

MAPPER
CLASS	RbtLigandSiteMapper
ENABLED	TRUE
GRIDSTEP	0.5
MAX_CAVITIES	1
MIN_VOLUME	100
NAME	MAPPER
RADIUS	6.0
REF_MOL	/data/NB_AT/rDock/tests/data/chemdiv_corrected/0.sdf
SMALL_SPHERE	1.5
TRACE	0
VOL_INCR	0.0

start*************************1***************************
start*************************10***************************
start*************************100***************************
start*************************101***************************
start*************************102***************************
start*************************103***************************
start*************************104***************************
代码
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Summary

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更新于 2024-04-18
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