ChEMBL & RDKit
Marrying Open Data with Open Tools

Rodrigo Ochoa
Mark Davies
Francis Atkinson
George Papadatos
John Overington

Outline••••Introduction to EBI and ChEMBL
Loading ChEMBL (PostgreSQL + RDKit)
Comparative studies between RDKit and Symyx
Web interface

INTRODUCTION

EBI structure

Literature and ontologies
CiteXplore, GO

Genomes
EnsemblEnsembl Genomes
EGA
Nucleotide sequence
ENA

Protein families,
motifs and domains
InterPro

Functional
genomics
ArrayExpress
Expression Atlas

Macromolecular
PDBeProtein activity
IntAct , PRIDE
Pathways
Reactome

Protein Sequences
UniProt• ChEMBL database• Curation• Interface• Research group

Chemogenomics
ChEMBL

Chemicalentities
ChEBI

Systems
BioModels
BioSamples

What is the ChEMBL database?
• A freely-available, curated source of small molecules,targets, assays and bioactivity data
• Core data is from the primary Med Chem literature• J. Med. Chem., Bioorg. Med. Chem. Lett., J. Nat. Prod.

• Information extracted••••

Compounds tested
Assays performed
Biological targets of assays
Activities of compounds in assays• Structures and data curated in-house to ensure quality

Compounds	  The image cannot be displayed. Your
computer may not have enough memory
to open the image, or the image may
have been corrupted. Restart yourcomputer, and then open the file again. Ifthe red x still appears, you may have todelete the image and then insert it again.

>Thrombin
MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIECQLW
RSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGE

Bioac3vi3es	  Ki = 4.5 nM

AssayTargets	  Compound

SAR Data
APTT = 11 min

ChEMBL 14 (latest version)
ChEMBL14	  Compounds:	  1,213,239	  	  Assays:	  644,734	  Targets:	  9,003	  Publica8ons:	  46,133	  Ac8vi8es:	  10,129,256	  Data	  sources:	  10	  Increase	  of	  >200,000	  compounds	  from	  literature	  since	  ChEMBL01	  ChEMBL interface

Chemical search in ChEMBL•A variety of sketchers (Marvin, JDraw, JME)

• ChEMBL chemical cartridge:
Symyx

LOADING CHEMBLRDKit overview• An open source collection of chemoinformatics andmachine-learning software written in C++ and Python• There is available a PostgreSQL cartridge(http://code.google.com/p/rdkit/wiki/DatabaseCartridgeReferenceDocumentation)

RDKit PostgreSQL cartridge• Molecular conversion (SMILES, SMARTS, CTAB)• Substructure search• Similarity SearchFingerprints: Morgan (ECFP-like), Atom-Pair, Torsion …
Similarity Coefficients: Tanimoto, Dice
• Molecular properties calculation

Bingo chemical cartridge• Open Source chemical cartridge provided by Indigo• Support PostgreSQL and Oracle schemas
Unfortunately it could not be compared with the others
chemical cartridges (bug reported in the Google groupforum)PostgreSQL ChEMBL version• ChEMBL originally is available in Oracle (Based on thisversion a MySQL dump file is available)
Task: Migrate the Oracle Schema to a PostgreSQL schema
Tool:
Open Source Kit of Perl libraries
Highly configurable
http://chembl.blogspot.co.uk/2012/08/chembl-postgresql.html

ChEMBL + cartridges

ChEMBLChEMBL version 14

Molecule
1.213.239 records

Chemical Cartridge# Moleculescorrectly built

RDKit

1.146.045

Symyx

1.147.790

Bingo

1.138.682

is_valid_ctab() RDKit function

mols_rdkit Table
fps_rdkit TableBuilding differences
Not built by RDKit (1565)
Non pure organics (1506)
Mainly boron clusters & organometallics

High valency (164; overlap with inorganics)	  Some are legitimate structures and	  probably should be handled:
Some need standardizing in
ChEMBL to e.g. charge-separatedform:
A few need fixing in
ChEMBL:Not built by Symyx (50)
Unusual isotopes (10); used in
PET, as tracers etc:

Duplicated structures (35):

No obvious reason for failure (5):1,145,994 parent structures built by both systems
i.e. problems with only a very small minority of structures!

COMPARISON

Cartridge comparison• Chemical cartridges: RDKit and Symyx• Type of queries: SMILES• Objective: Detect discrepancies and the reasons behindthem.
• RDKit configuration:
Version: 2012_06
OS: Linux Ubuntu 12.04 64 bits (Virtual Machine)
PostgreSQL version: 9.1.4• Symyx configuration:
Version: 6.2
OS: Red Hat 5.8 64 bits (Server)
Oracle version: 11.1.0.7.0

Fragment library• From a set of ChEMBL molecules, RECAP* algorithm was applied.
• A filter based on the number of heavy atoms and molecular weightwas done using the RDKit nodes in KNIME• 40 fragments were chosen* Lewell XQ, Judd DB, Watson SP, Hann MM. RECAP - Retrosynthetic Combinatorial Analysis Procedure: A powerful new technique for identifying "privileged molecular fragments with useful applications in combinatorial chemistry. Journal of Chemical Information and Computer Sciences 1998, 38:511-522.

KNIME protocol

KNIME results
RDKit

BothSymyx

Some results …
Fragment	  1	  5	  9	  14	  Molecule	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  RDKit	  no	  Symyx	  Symyx	  no	   Join	  Symyx	  RDKit	  RDKit	  Total	  RDKit	  Total	  Symyx	  1595	  5565	  25404	  26999	  30969	  52	  268	  18247	  18299	  18515	  263	  6	  199	  462	  205	  62546	  2455	  73510	  136056	  75965	  Aromaticity perception: benzene
RDKit SMARTS: c1ccccc1

Symyx molfile:• 1445 structures found by RDKit but not by Symyx• Due to differing aromaticity models• Sometimes highlights unusual choice of tautomer

Aromaticity perception: pyridone
RDKit SMARTS: c1cccnc1=OSymyx molfile:• 6760 structures hit by RDKit but not by Symyx
Bond is now aromatic anddoesn’t match double bond inquery• Can adjust Symyx query to catch these:• Reduces discrepancy to 179…

Aromaticity models•Differing aromaticity models mean it can be difficult tocode queries that give same hits in both systems
Not a new problem!
e.g. Symyx/MDL vs. Daylight•

MarvinSketch can be used to generate SMARTS
queries appropriate for RDKit
User would need to be aware of issues if using advanced queryfeatures•

Unlikely to be a real problem once transitioning users
become accustomed to new conventions

Stereochemistry
Chiral matching not currently handled by RDKit
Symyx can handle chiral queries
However, there are issues with chiral searching in ChEMBL• Some inconsistences in setting of chiral flag
• Issue is being investigatedBest avoided for now !!!

INTERFACE

Interface• Substructure, Similarity search against ChEMBL database• Additionally, calculation of molecular properties• Substructure search using SMARTS, SMILES or MolFiles• Query results using substructure search

Generatedwith RDKit• Similarity search using different Fingerprints and Similarity Coefficients• Query results using Similarity search• Compound report (with links to the ChEMBL website)• Molecular properties calculation• Similarity search RESTful web service (also for substructure)

Summary and future plans• Provide a complete PostgreSQL version of ChEMBL per new
release, available in the FTP site
https://www.ebi.ac.uk/chembldb/index.php/downloads• Integrate the Open Chemical Cartridge (RDKit) with open
chemogenomics data (ChEMBL) in a Virtual Machine available forusers, who can personalize the configuration and update the data.
• Provide a personal interface, with web applications and RESTful
web services.

Acknowledgements

Training Opportunities

Symyx

Mark Davies
Francis Atkinson
George Papadatos
John Overington