Small Molecules Resources at the EBI Dr. Louisa Bellis Chemical Content Curator, ChEMBL Group EMBL-EBI, UK Bioinformatics Resources for Immunologists 6th September 2013 Services | Research | Training | Industry Agenda • Introduction • Small molecule resources • ChEBI • ChEMBL • Searching and browsing • Hands-on Exercises Small Molecules within Bioinformatics Genomes Literature Expressions Nucleotide sequences Protein sequences Protein domains, families Enzymes 3D structures Small molecules Pathways Systems Annotation of bioinformatics data • Essential for capturing understanding and knowledge associated with core data • Often captured in free text, which is easier to read and better for conveying understanding to a human audience, but… • Difficult for computers to parse • Quality varies from database to database • Terminology used varies from annotator to annotator • Towards annotation using standard vocabularies: ontologies within bioinformatics Small Molecule Databases can be used to: • Investigate historical compounds and associated bioactivity data. • Create Structure-Activity Relationships (SARs) • Direct synthesis • Direct end product testing ChEBI and ChEMBL What is ChEBI? • Chemical Entities of Biological Interest • Freely available • Focused on ‘small’ chemical entities (no proteins or nucleic acids) • • • • Illustrated dictionary of chemical nomenclature High quality, manually annotated Provides chemical ontology ~39,000 ChEBI 3* compounds Access ChEBI at http://www.ebi.ac.uk/chebi/ ChEBI Data Overview Nomenclature Ontology caffeine 1,3,7-trimethylxanthine methyltheobromine metabolite CNS stimulant trimethylxanthines Chemical data Database Xrefs Formula: C8H10N4O2 Charge: 0 Mass: 194.19 MSDchem: CFF KEGG DRUG: D00528 Chemical Informatics InChI=1/C8H10N4O2/c1-10-4-9-65(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 SMILES: CN1C(=O)N(C)c2ncn(C)c2C1=O Visualisation CHEBI COMPOUND PAGE ChEBI Chemical Structures • Chemical structure may be interactively explored using MarvinView applet • Available in formats • Image • Molfile • InChI and InChIKey • SMILES Automatic Cross-references The ChEBI ontology Organised into three sub-ontologies, namely • Molecular structure ontology • Subatomic particle ontology • Role ontology (R)-adrenaline Molecular structure ontology Role ontology ChEBI ontology relationships • Generic ontology relationships • Chemistry-specific relationships Viewing ChEBI ontology What is ChEMBL? • Database of bioactive, drug-like small molecules. • Store 2D structures, calculated properties (logP, mol weight, Lipinski etc) • Contains abstracted bioactivity data, e.g. binding data and IC50, from multiple primary scientific journals • Covers about 33 years of compound synthesis and testing • Annotated FDA-approved drugs Access ChEMBL at https://www.ebi.ac.uk/chembldb/ Data Statistics • • • • Focused towards compounds with drug-like properties by extraction from medicinal chemistry journals Includes small molecules (~92%) and peptides (~7%) Abstracted from 50,095 papers across 47 journals 1,487,579 compound records (~450,000 directly from PubChem) • • 11,420,351 activities (>6.0 million directly from PubChem) • • • 1,295,510 distinct compound structures binding measurements, functional assays and ADMET 9,844 targets, with over 5,400 protein targets and over 2,440 human targets Deposition of PubChem Substances and Bioassay assays ChEMBL Data Overview Compound H N N H O Target N H N MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEALE SSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGA DLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRL AVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETG DGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMS PWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIH PRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQV VNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKY GFYTHVFRLKKWIQKVIDQFGE N H N >Thrombin N O H O Bioactivity Compound Ki=4.5 nM Assay SAR Data APTT 11 min Clinical Trials Target Discovery Lead Discovery •Target identification •Microarray profiling •Target validation •Assay development •Biochemistry •Clinical/Animal disease models •High-throughput Screening (HTS) •Fragment-based screening •Focused libraries •Screening collection Lead Optimisation •Medicinal Chemistry •Structure-based drug design •Selectivity screens •ADMET screens •Cellular/Animal disease models •Pharmacokinetics Preclinical Development Phase 1 •Toxicology •In vivo safety pharmacology •Formulation •Dose prediction PK tolerability Discovery Med. Chem. SAR Phase 2 Phase 3 Efficacy Safety & Efficacy Development Launch Indication Discovery & expansion Use Clinical Candidates Drugs ~15,000 candidates ~2,400 drugs ChEMBL database > 10,000,000 bioactivities > 1,300,000 compounds ~30,000 distinct lead series ChEMBL Target Types Molecular Nucleic acid Non-molecular Protein Cell-line HEK293 cells Tissue Subcellular-fraction Organism Nervous Mitochondria DNA Single Protein Protein Complex PDE5 Nicotinic acetylcholine receptor Protein Family Muscarinic receptors Drosophila CHEMBL COMPOUND PAGE Clickable structure Drug Information Structural Representations ChEMBL --> ChEBI Link: ChemSpider Links: The link works both ways. They link TO ChemSpider and FROM ChemSpider. They link on Standard InChI Wikipedia Links: We also have links with Wikipedia. These also use the Standard_Inchi as the common identifier. These links will link to the Compound Report Card in ChEMBL. Searching and Browsing Chemical names • Common or trivial names are those that are highly used. • Advantages of common names include simplicity, easy to pronounce, universally recognised • The main disadvantage is ambiguity – the same common name may refer to more than one type of chemical. • Fluorene • Fluorine Systematic names • A systematic name is one which corresponds to the chemical structure such that the structure can be determined from the name, e.g. 1,2-dimethyl-naphthalene • Software packages exist which can generate structures from the systematic names (e.g. ACD/Name, ChemOffice, MarvinSketch). • More than one correct systematic name can be assigned to the same molecular structure, depending on the manner in which naming rules are applied (e.g. IUPAC names). Examples of common and systematic names Common names caffeine Systematic names 1,3,7-trimethyl-3,7-dihydro-1Hpurine-2,6-dione guaranine 7-methyltheophylline theine 1,3,7-trimethyl-2,6dioxopurine The ChEBI web service • Programmatic access to a ChEBI entry • SOAP based Java implementation • Clients currently available in Java and perl • Methods include: • getLiteEntity • getCompleteEntity and getCompleteEntityByList • getOntologyParents • getOntologyChildren and getAllOntologyChildrenInPath • getStructureSearch • Documented at http://www.ebi.ac.uk/chebi/webServices.do. Web services • Allow users to create their own applications to query data User application The ChEBI web service • Programmatic access to a ChEBI entry • SOAP based Java implementation • Clients currently available in Java and perl • Methods • getLiteEntity • getCompleteEntity and getCompleteEntityByList • getOntologyParents • getOntologyChildren and getAllOntologyChildrenInPath • getStructureSearch • Documented at http://www.ebi.ac.uk/chebi/webServices.do. Web service client object model getLiteEntity getCompleteEntity getOntology (Parents and Children) ChEMBL Web Services • Programmatic access to the ChEMBL database • Provide Java, Perl and Python scripts to help you get started with the ChEMBL RESTful Web Service API • Can be used to bring back compounds, lists of compounds, images, targets and assays • https://www.ebi.ac.uk/chembldb/index.php/ws Examples of Web Services INTERFACE SEARCHING ChEBI simple and advanced text search AND, OR and BUT NOT Narrow to category Structure drawing tools Search options Search Results Hover-over for a larger structure Click to go to entry page Types of structure search • Identity – based on InChI InChI=1/H2O/h1H2 • Substructure – uses fingerprints to narrow search range, then performs full substructure search algorithm 0010110010 1010110111 • Similarity – based on Tanimoto coefficient calculated between the fingerprints Tanimoto(a,b) = c / (a+b-c) a 0010110010 b 1010110111 = 4 / (4+7-4) = 0.57 Browse via Periodic Table Molecular entities / Elements Navigate via links in ontology Click to follow ontology links ChEMBL Interface Searching: • Keywords • Compound name • Trade Name • Synonym • Structure • Exact match • Substructure • SMILES • Single or a list of SMILES Keyword searches. Can use * as a wildcard Can search with a list of ChEMBL IDs, or Keywords or SMILES Run substructure and similarity searches Types of Compound Names To Use • ChEMBL captures all compound names, compound keys and synonyms from the papers. • Synonyms can be taken from the publications or are curated from other sources (e.g. NCBI website). • Curated and extracted synonyms in ChEMBL_16 > 660,000 • Types of synonyms captured include: • Research codes • FDA alternative names • Trade Names (not for combinations of drugs) • INN, BAN, JAN, USAN Protein Sequence Search • More precise method for identifying targets • Input is a protein sequence of interest • Uses BLAST* algorithm to perform pair-wise comparisons between input sequence and all proteins in the Target Dictionary, to find most closely related matches • Results are scored according to similarity to input sequence (determined by number of amino acids that are identical or have similar properties) *Altschul SF et al., J Mol Biol. 215(3), p403-10 (1990). Find a protein sequence of interest http://www.uniprot.org Select entry of interest Retrieve sequence in fasta format Paste in a FASTA file and run a search to fetch matching targets Can also browse using the Taxonomy Family Tree browser Search box for keyword searching Browse Drugs Tab Able to search the approved drugs using keywords WHY USE ChEBI AND ChEMBL? I want to find data and information on the target, IRAK4. I also want to find out about the compounds that have been tested against this target. But where would I start?.... Identifying Chemical Tools • Search ChEMBL for protein of interest • Simple text search against protein names/synonyms OR • Browse protein family tree OR • Sequence search using BLAST (can find related proteins) • Identify compounds active against this protein • Sort/filter by relevant activity types and potency • E.g., retrieve compounds with IC50/Ki < 100nM • Retrieve other data for these compounds • Structures, chemical properties, other activities Compound Properties and Selectivity • ChEMBL stores a wide range of calculated compound properties (e.g., mol wt, logP, RO5 violations) • Can be used to identify compounds most likely to have good in vivo properties (Absorption, Distribution, Metabolism, Excretion) • Contains activity information against liability targets (e.g., cytochrome P450s, HERG K+ channel) • If compounds have been tested in these assays, can avoid those with potential toxicity issues • Contains data on a wide range of targets • If compounds have been tested against multiple targets, can get an idea of their selectivity (important for validation studies) DOWNLOAD AND ANALYSIS OF RESULTS • The compound results can be downloaded as an *.SDFile. • The bioactivity data can be downloaded as *.XLS or a TAB file (tab-delimited) Activity types and values Assay details Literature references You can use the standard Excel filtering options to filter the results Downloads and programmatic access Downloading ChEBI flavours • All downloads come in two flavours • 3 star only entries (manually annotated ChEBI entries) • 2 and 3 star entries (manually annotated ChEBI, ChEMBL and user submissions) Downloading ChEBI • OBO file • Use on OBO-edit • SDF File • Chemistry software compliant such as Bioclipse • Flat file, tab delimited • Import all the data into Excel • Parse it into your own database structure • Oracle binary dumps • Import into an oracle database • Generic SQL insert statements • Import into MySQL or postgresql database Downloading ChEMBL Help and Feedback • Email addresses for support queries and feedback • General questions and feedback on ChEMBL interface: chembl-help@ebi.ac.uk • Reporting of data errors: chembl-data@ebi.ac.uk • General questions, support and feedback on ChEBI chebi-help@ebi.ac.uk Thank you Services | Research | Training | Industry