Can machine learn important feature from SMILES?

Today I found challenging article in arxiv.
It describes about SMILES2Vec.
You know word2vec is very attractive and major application for ML area and SMILES2Vec has same concept.
It converts smiles to vector and learn which character is important. The author use “black box” models for building model. I am not sure about “black box” model but I think it likes leave one out. The method masks some features, builds model and finds important features.

To use the method, SMILES2Vec can find important characters in the given smiles.
They found CNN-GRU model gives best result for solubility prediction. My question is … Why convolution of SMILES work fine???
My opinion is that solubility or logP depends on the presence or absence of substituents such as hydroxyl or amino groups, they do not strongly depend on the position some case. So I think the method is interesting but difficult to predict biological affinity.

SMILES strings is major input format for deep learning area. Also I often use SMILES. 😉 But I want to find another format for DL.

ref for black box model


QED calculation on RDKit 2017.09 #RDKit

QED (quantitative estimate of drug-likeness ) is an one of score of drug likeness reported by Hopkins group.

The author provided QED calculator for pipeline pilot. So QED could not calculate without pipeline pilot.
But, now we can calculate QED by using RDKit!
RDKit 201709 was implemented QED descriptor. Seems good, let’s use the function.
It is very simple. Just call qed!. I used dataset the same as yesterday.

import os
from rdkit.Chem import rdBase, RDConfig
from rdkit import Chem
from rdkit.Chem import PandasTools
from rdkit.Chem.Draw import IPythonConsole
from rdkit.Chem.Descriptors import qed
print( rdBase.rdkitVersion )

sdfpath = os.path.join( RDConfig.RDDocsDir, "Book/data/cdk2.sdf" )
mols = [ m for m in Chem.SDMolSupplier( sdfpath ) if m != None ]
df = PandasTools.LoadSDF( sdfpath )
print( len( mols ))

df.head( 2 )

df[ "QED" ] =  df.ROMol.apply( qed )
df.head(2 )

from rdkit.Chem import QED
for mol in mols:
    print( mol ) )

It is easy isn’t it ?
I pushed sample code to my repository.
By the way, original QED score was based on ChEMBL ver 09. So, dataset is old. Does the score show difference when we use new version of ChEMBL ? 😉

Create MMPDB ( matched molecular pair )!

Matched molecular pair analysis is very common method to analyze SAR for medicinal chemists. There are lots of publications about it and applications in these area.
I often use rdkit/Contrib/mmpa to make my own MMP dataset.
The origin of the algorithm is described in following URL.

Yesterday, good news announced by @RDKit_org. It is release the package that can make MMPDB.
I tried to use the package immediately.
This package is provided from github repo. And to use the package, I need to install apsw at first. APSW can install by using conda.
And the install mmpdb by python script.

iwatobipen$ conda install -c conda-forge apsw
iwatobipen$ git clone
iwatobipen$ cd mmpdb
iwatobipen$ python install

After success of installation, I could found mmpdb command in terminal.
I used CYP3A4 inhibition data from ChEMBL for the test.
I prepared two files, one has smiles and id, and the another has id and ic50 value.
* means missing value. In the following case, I provided single property ( IC50 ) but the package can handle multiple properties. If reader who is interested the package, please show more details by using mmpdb –help command.

iwatobipen$ head -n 10 chembl_cyp3a4.csv 
iwatobipen$ head -n 10 prop.csv 
924282	*
605	*
1698776	*
59721	19952.62
759749	2511.89
819161	2511.89

mmdb fragment has –cut-smarts option.
It seems attractive for me! 😉
–cut-smarts SMARTS alternate SMARTS pattern to use for cutting (default:
[CH2])]’), or use one of: ‘default’,
‘cut_AlkylChains’, ‘cut_Amides’, ‘cut_all’,
‘exocyclic’, ‘exocyclic_NoMethyl’
Next step, make mmpdb and join the property to db.

# run fragmentation and my input file has header, delimiter is comma ( default is white space ). Output file is cyp3a4.fragments.
# Each line of inputfile must be unique!
iwatobipen$ mmpdb fragment chembl_cyp3a4.csv --has-header --delimiter 'comma' -o cyp3a4.fragments
# rung indexing with fragmented file and create a mmpdb. 
iwatobipen$ mmpdb index cyp3a4.fragments -o cyp3a4.mmpdb

OK I got cyp3a4.mmpdb file. (sqlite3 format)
Add properties to a DB.
Type following command.

iwatobipen$ mmpdb loadprops -p prop.csv cyp3a4.mmpdb
Using dataset: MMPs from 'cyp3a4.fragments'
Reading properties from 'prop.csv'
Read 1 properties for 17143 compounds from 'prop.csv'
5944 compounds from 'prop.csv' are not in the dataset at 'cyp3a4.mmpdb'
Imported 5586 'STANDARD_VALUE' records (5586 new, 0 updated).
Generated 83759 rule statistics (1329408 rule environments, 1 properties)
Number of rule statistics added: 83759 updated: 0 deleted: 0
Loaded all properties and re-computed all rule statistics.

Ready to use DB. Let’s play with the DB.
Identify possible transforms.

iwatobipen$ mmpdb transform --smiles 'c1ccc(O)cc1' cyp3a4.mmpdb --min-pair 10 -o transfom_res.txt
iwatobipen$ head -n3 transfom_res.txt 
1	CC(=O)NCCO	[*:1]c1ccccc1	[*:1]CCNC(C)=O	0	59SlQURkWt98BOD1VlKTGRkiqFDbG6JVkeTJ3ex3bOA	1049493	14	3632	5313.6	-0.71409	-0.033683	-6279.7	498.81	2190.5	7363.4	12530	-2.5576	0.023849
2	CC(C)CO	[*:1]c1ccccc1	[*:1]CC(C)C	0	59SlQURkWt98BOD1VlKTGRkiqFDbG6JVkeTJ3ex3bOA	1026671	20	7390.7	8556.1	-1.1253	-0.082107	-6503.9	-0	8666.3	13903	23534	-3.863	0.0010478

Output file has information of transformation with statistics values.
And the db can use to make a prediction.
Following command can generate two files with prefix CYP3A-.

iwatobipen$ mmpdb predict --reference 'c1ccc(O)cc1' --smiles 'c1ccccc1' cyp3a4.mmpdb  -p STANDARD_VALUE --save-details --prefix CYP3A
iwatobipen$ head -n 3 CYP3A_pairs.txt
rule_environment_id	from_smiles	to_smiles	radius	fingerprint	lhs_public_id	rhs_public_id	lhs_smiles	rhs_smiles	lhs_value	rhs_value	delta
868610	[*:1]O	[*:1][H]	0	59SlQURkWt98BOD1VlKTGRkiqFDbG6JVkeTJ3ex3bOA	1016823	839661	C[C@]12CC[C@@H]3[C@H](CC[C@H]4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@H]2C(=O)CO	CC(=O)[C@@H]1CC[C@H]2[C@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@@]21C	1000	15849	14849
868610	[*:1]O	[*:1][H]	0	59SlQURkWt98BOD1VlKTGRkiqFDbG6JVkeTJ3ex3bOA	3666	47209	O=c1c(O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12	O=c1cc(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12	15849	5011.9	-10837
iwatobipen$ head -n 3 CYP3A_rules.txt 
rule_environment_statistics_id	rule_id	rule_environment_id	radius	fingerprint	from_smiles	to_smiles	count	avg	std	kurtosis	skewness	min	q1	median	q3	max	paired_t	p_value
28699	143276	868610	0	59SlQURkWt98BOD1VlKTGRkiqFDbG6JVkeTJ3ex3bOA	[*:1]O	[*:1][H]	16	-587.88	14102	-0.47579	-0.065761	-28460	-8991.5	-3247.8	10238	23962	0.16674	0.8698
54091	143276	1140189	1	tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8	[*:1]O	[*:1][H]	15	-1617	13962	-0.25757	-0.18897	-28460	-9534.4	-4646	7271.1	23962	0.44855	0.66062

It is worth that the package ca handle not only structure based information but also properties.
I learned a lot of things from the source code.
RDKit org is cool community!
I pushed my code to my repo.

original repo URL is
Do not miss it!

3d conformer fingerprint calculation using RDKit # RDKit

Recently, attractive article was published in ACS journal.
The article describes how to calculate 3D structure based fingerprint and compare some finger prints that are well known in these area.
New method called “E3FP” is algorithm to calculate 3D conformer fingerprint like Extended Connectivity Fingerprint(ECFP). E3FP encodes information only atoms that are connected but also atoms that are not connected.

The author showed several examples. Very similar in 2D but not similar in 3D and vice versa.
Also compare E3FP similarity and ROCS score( TANIMOTO COMBO ) and showed good performance.
I was interested in the fingerprint. Fortunately, the author published the code in Anaconda cloud!!!!!!!
Install it and use it ASAP. ;-D
I am mac user, so installation is very very very easy! Just type.
I found some tips to use the package.
At first, molecules need _Name property to perform calculation.
Second, mol_from_sdf can read molecule from sdf but the function can not read sdf that has multiple molecules. So, I recommend to use molecule list instead of SDF.

conda install -c sdaxen sdaxen_python_utilities
conda install -c keiserlab e3fp

I used CDK2.sdf for test.
E3FP calculates unfolded finger print. But it can convert folded fingerprint and rdkit fingerprint using flod and to_rdkit function.

%matplotlib inline
import pandas as pd
import numpy as np
from rdkit import Chem
from e3fp.fingerprint.generate import fp, fprints_dict_from_mol
from e3fp.conformer.generate import generate_conformers
from rdkit.Chem.Draw import IPythonConsole
from rdkit.Chem import Draw
from rdkit.Chem import DataStructs
from rdkit.Chem import AllChem
# this sdf has 3D conformer, so I do not need to generate 3D conf.
mols = [ mol for mol in Chem.SDMolSupplier( "cdk2.sdf", removeHs=False ) ]
fpdicts = [ fprints_dict_from_mol( mol ) for mol in mols ]
# get e3fp fingerprint
# if molecule has multiple conformers the function will generate multiple fingerprints.
fps = [ fp[5][0] for fp in fpdicts]
# convert to rdkit fp from e3fp fingerprint
binfp = [ fp.fold().to_rdkit() for fp in fps ]
# getmorganfp
morganfp = [ AllChem.GetMorganFingerprintAsBitVect(mol,2) for mol in mols ]

# calculate pair wise TC
df = {"MOLI":[], "MOLJ":[], "E3FPTC":[], "MORGANTC":[],"pairidx":[]}
for i in range( len(binfp) ):
    for j in range( i ):
        e3fpTC = DataStructs.TanimotoSimilarity( binfp[i], binfp[j] )
        morganTC = DataStructs.TanimotoSimilarity( morganfp[i], morganfp[j] )
        moli = mols[i].GetProp("_Name")
        molj = mols[j].GetProp("_Name")
        df["MOLI"].append( moli )
        df["MOLJ"].append( molj )
        df["E3FPTC"].append( e3fpTC )
        df["MORGANTC"].append( morganTC )
        df["pairidx"].append( str(i)+"_vs_"+str(j) )

The method is fast and easy to use. Bottle neck is how to generate suitable conformer(s).
Readers who interested in the package, please check the authors article.

I pushed my sample code to my repo.


I want to retrieve relationship between TID and PREF_NAME in specific case from ChEMBL DB.
SQL query is following.

  3                       JOIN ASSAYS USING (ASSAY_ID)
  4                       JOIN TARGET_DICTIONARY USING (TID)
  5                       WHERE STANDARD_TYPE = 'Ki'
  6                       AND STANDARD_VALUE IS NOT NULL
  7                       AND STANDARD_RELATION = '='
  8                        )
  9         TO '/path/td.csv'
 10         ( FORMAT CSV )

I ran the sql and got result like ….

3,Phosphodiesterase 5A
6,Dihydrofolate reductase
7,Dihydrofolate reductase
8,Tyrosine-protein kinase ABL
9,Epidermal growth factor receptor erbB1
13,Beta-lactamase TEM
14,Adenosine deaminase
15,Carbonic anhydrase II
19,Estrogen receptor alpha
23,Plasma kallikrein
24,HMG-CoA reductase
25,Glucocorticoid receptor
28,Thymidylate synthase
30,Aldehyde dehydrogenase
35,Insulin receptor
36,Progesterone receptor
41,Alcohol dehydrogenase alpha c



Installing TensorFlow on Mac OX X with GPU support

Yesterday, I tried to install tensorflow-gpu on my mac.
My PC is MacBook Pro (Retina, 15-inch, Mid 2014). The PC has NVIDA GPU.
OS is Seirra.
Details are described in following URL.

I installed tensorflow directly by using pip command.

 $ pip install --upgrade tensorflow-gpu  # for Python 2.7 and GPU #for python2
 $ pip3 install --upgrade tensorflow-gpu # for Python 3.n and GPU  #for python2

Almost done, but not finished yet.
To finish the installation, I need to disable System Integrity Protection (SIP).
To do that I need follow these steps.

Restart my Mac.
Before OS X starts up, hold down Command-R and keep it held down until you see an Apple icon and a progress bar. ...
From the Utilities menu, select Terminal.
At the prompt type exactly the following and then press Return: csrutil disable.

I tested following code.

import tensorflow as tf

# Creates a graph.
a = tf.constant([1.0, 2.0, 3.0, 4.0, 5.0, 6.0], shape=[2, 3], name='a')
b = tf.constant([1.0, 2.0, 3.0, 4.0, 5.0, 6.0], shape=[3, 2], name='b')
c = tf.matmul(a, b)

# Creates a session with log_device_placement set to True.
sess = tf.Session(config=tf.ConfigProto(log_device_placement=True))

# Runs the op.

And the results seems tensorflow can use GPU.

iwatobipen$ python
2017-06-13 22:24:28.952288: W tensorflow/core/platform/] The TensorFlow library wasn't compiled to use SSE4.2 instructions, but these are available on your machine and could speed up CPU computations.
2017-06-13 22:24:28.952314: W tensorflow/core/platform/] The TensorFlow library wasn't compiled to use AVX instructions, but these are available on your machine and could speed up CPU computations.
2017-06-13 22:24:28.952319: W tensorflow/core/platform/] The TensorFlow library wasn't compiled to use AVX2 instructions, but these are available on your machine and could speed up CPU computations.
2017-06-13 22:24:28.952323: W tensorflow/core/platform/] The TensorFlow library wasn't compiled to use FMA instructions, but these are available on your machine and could speed up CPU computations.
2017-06-13 22:24:29.469570: I tensorflow/stream_executor/cuda/] OS X does not support NUMA - returning NUMA node zero
2017-06-13 22:24:29.470683: I tensorflow/core/common_runtime/gpu/] Found device 0 with properties:
name: GeForce GT 750M
major: 3 minor: 0 memoryClockRate (GHz) 0.9255
pciBusID 0000:01:00.0
Total memory: 2.00GiB
Free memory: 1.80GiB
2017-06-13 22:24:29.470713: I tensorflow/core/common_runtime/gpu/] DMA: 0
2017-06-13 22:24:29.470720: I tensorflow/core/common_runtime/gpu/] 0:   Y
2017-06-13 22:24:29.470731: I tensorflow/core/common_runtime/gpu/] Creating TensorFlow device (/gpu:0) -> (device: 0, name: GeForce GT 750M, pci bus id: 0000:01:00.0)
Device mapping:
/job:localhost/replica:0/task:0/gpu:0 -> device: 0, name: GeForce GT 750M, pci bus id: 0000:01:00.0
2017-06-13 22:24:29.490805: I tensorflow/core/common_runtime/] Device mapping:
/job:localhost/replica:0/task:0/gpu:0 -> device: 0, name: GeForce GT 750M, pci bus id: 0000:01:00.0

MatMul: (MatMul): /job:localhost/replica:0/task:0/gpu:0
2017-06-13 22:24:29.495363: I tensorflow/core/common_runtime/] MatMul: (MatMul)/job:localhost/replica:0/task:0/gpu:0
b: (Const): /job:localhost/replica:0/task:0/gpu:0
2017-06-13 22:24:29.495384: I tensorflow/core/common_runtime/] b: (Const)/job:localhost/replica:0/task:0/gpu:0
a: (Const): /job:localhost/replica:0/task:0/gpu:0
2017-06-13 22:24:29.495395: I tensorflow/core/common_runtime/] a: (Const)/job:localhost/replica:0/task:0/gpu:0
[[ 22.  28.]
 [ 49.  64.]]

ref URL

Open drug discovery toolkit for python

Recently There are lots of python libraries for chemoinformatics and machine learning. One of my favorites is RDKit. 😉
These area is still active. And today I tried new library named “ODDT” open drug discovery toolkit.
Reference URL is
ODDT is well documented in ⭐️
Oddt is implemented shape and electronic similarities!! I have never known the open source library that implemented electronic similarity. And the library also implemented function that can detect protein ligand interaction.
So, I tried to use oddt.
First, calculation of some similarities codes are below.
To calculate electroshape, just use shape.electroshape method.

from oddt import toolkit
from oddt import shape
from oddt import fingerprints
from rdkit.Chem import Draw
mols = toolkit.readfile( 'sdf', 'cdk2.sdf' )
mols = [ m for m in mols ]
print(len( mols ))
[out] 47
e_shapes = [ shape.electroshape( mol ) for mol in mols ]
usrcats = [ shape.usr_cat( mol ) for mol in mols ]
usrs = [ shape.usr( mol ) for mol in mols ]

To calculate similarity, just use usr_similarity method.

for i in range( len( mols[ :5 ] ) ):
    for j in range( i ):
        e_sim = shape.usr_similarity( e_shapes[i], e_shapes[j] )
        usrcat_sim = shape.usr_similarity( usrcats[i], usrcats[j] )
        usr_sim = shape.usr_similarity( usrs[i], usrs[j])
        print( i, j, "e_shim", e_sim, 'usrcat_sim', usrcat_sim,'usr_sim',usr_sim )
1 0 e_shim 0.879372074943 usrcat_sim 0.742055515733 usr_sim 0.676152090576
2 0 e_shim 0.865690221755 usrcat_sim 0.428271350002 usr_sim 0.686898339111
2 1 e_shim 0.896725884564 usrcat_sim 0.481233989554 usr_sim 0.763231432529
3 0 e_shim 0.766813506629 usrcat_sim 0.609482600031 usr_sim 0.463058006246
3 1 e_shim 0.7349875959 usrcat_sim 0.548950403001 usr_sim 0.459194544856
3 2 e_shim 0.715411936912 usrcat_sim 0.360330544106 usr_sim 0.424537194619
4 0 e_shim 0.810683079155 usrcat_sim 0.62174869307 usr_sim 0.61705827303
4 1 e_shim 0.774077718141 usrcat_sim 0.635441642096 usr_sim 0.694498992613
4 2 e_shim 0.755174336047 usrcat_sim 0.394074936141 usr_sim 0.618174238781
4 3 e_shim 0.931446873697 usrcat_sim 0.780733001638 usr_sim 0.562721912484

OK, next check protein-ligand contact. To do that I prepare protein and ligand file from pdb.
And the read each files and preform calculation.

from oddt import interactions
pdb1 = next(toolkit.readfile( 'pdb', '1atp_apo.pdb'))
pdb1.protein = True
ligand = next( toolkit.readfile('sdf', 'atp.sdf'))
proteinatoms, ligandatoms, strict=interactions.hbonds( pdb1, ligand )
array(['GLU', 'GLU', 'GLU', 'GLU', 'HOH', 'HOH', 'ARG', 'VAL', 'SER',
       'ALA', 'HOH', 'PHE', 'GLY', 'LYS', 'HOH', 'HOH', 'THR'], 

ODDT also can calculate protein-ligand interaction fingerprint.

IFP = fingerprints.InteractionFingerprint( ligand, pdb1)
print( IFP )
[out] array([0, 0, 0, ..., 0, 0, 0], dtype=uint8)

I think oddt is very nice toolkit for chemoinformatics.
I uploaded my code on my github repo.