USING EMBL-EBI CHEMOGENOMICS RESOURCES TO SUPPORT DRUG DISCOVERY RESEARCH - ANNE HERSEY CHEMBL GROUP, EMBL-EBI
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Using EMBL-EBI Chemogenomics
Resources to Support Drug Discovery
Research
Anne Hersey
ChEMBL Group, EMBL-EBI
ahersey@ebi.ac.uk
Outline of Talk
How can chemogenomics resources help answer:
• Which compound?
• Does it get to site of action?
• Is it safe?
Focus on:
• ChEMBL – Bioactivity database
• SureChEMBL – Patent Database
• UniChem – compound cross referencing
• Examples by ChEMBL Users
2
Drug Discovery Pipeline
Hit Lead
Target identification Pre-Clinical Clinical
Identification Optimisation
• Target Identification (What to work on?)
• Target to Disease links - Open Targets
• Hit identification/Lead Optimisation (Which compound?)
• Bioactivity Data - ChEMBL, SureChEMBL, UniChem
• Pre-clinical data (Is it safe, does it get there?)
• in-vivo exposure and toxicity data - ChEMBL
• Clinical Candidates & Approved Drugs (What works?)
• Efficacy target, disease annotation - ChEMBL
3
ChEMBL Database Content
Scientific literature Public databases
• Medicinal chemistry
• ADME relevant • Confirmatory assays
• Agrochemicals
• Reviews etc
Patents
• Bioactivities
Underexplored
Deposited data sets targets (IDG)
Toxicity reference data sets
1,800,000
compds
Clinical research compound sets
• Black box warning/withdrawals
• Therapeutic mechanism/indications
• Molecule features
ChEMBL Data and Curation Pipeline
Parent
Compounds structures
Salt Property
Documents standardisation aLogP 0.74
removal calculation HBA 2
HBD 1
MWt 155.2
• Functional groups Ro5 0
• Drawing conventions RTB 2
HAtoms 11
pKa 7.84
LogD -0.78
QED 0.55
…
Linked by
Activities compound hierarchy
Assays
Cmpd A
Cmpd B
IC50 = 0.01 µM Molfiles Compound registration
Assay 1
• Depictions
Compounds
InChI=1S/C14H9ClF2N2O2/c15-8-4-6-9…
Cmpd C
InChI=1S/C15H12N2O3/c18-17(19)14-9…
Assays Cmpd A EC50 = 1 µM
• Chemistry cartridge InChI=1S/C8H13NO2/c1-9-5-3-4-7(6-9)8…
InChI=1S/C8H13NO2.BrH/c1-9-5-3-4-7(6…
Assay 2
Cmpd C
Cmpd C Assay 3 ED50 = 10 mg/kg
Activity curation
1 2 3
• Unit standardisation Compound
• Outlier flagging information
Assay
Target description
assignment (free text) Ontology annotation Experimental
• BAO data Molecule
Activities dictionary
Assays hierarchy
• UniProt Ontology annotation
Target • EBI Complex Portal • GO terms properties
registration • IUPhar Target
dictionary
PDE5 HEK293 Rattus • Cell Dictionary Collated from various Documents
cells norvegicus existing ontologies Target
• Tissue Dictionary information
• NCBI taxonomy Source information
SureChEMBL Pipeline
Fully automated pipeline
Chemical entity recognition Name to structure
and OCR correction (5 methods)
Image to structure
(1 method) Chemical
registration
Patent data feed
(IFI claims)
Complex work units
WO,
EP (app. and granted), 20 million unique compounds
US (app. and granted),
JP (English abstracts) 80,000 new compounds per month
UniChem – Compound Mapping across Resources
UniChem
156 million compounds
35 sources
Web Services
Web
Inter
face
l oads
own
D
7
Which Target and Compound?
Marketed drugs Human drug targets
~ 3,000 ~800
Research compounds Human targets with bioactive molecules
~1,800,000 ~3,500
~1.8 million
Which Target and Compound?
Other species
Non protein targets
Human Proteins ~20,000
Patents
Targets
Bioactivity Data
UniChem (10^8)
GDB17 (10^11)*
Approved Drugs All (10^33)**
Compounds
9 *JL Reymond JCIM 2013, **PG Polishchuk JCAMD 2013
Targets
Bioactive Molecule Space
Compounds
Data matrix is far from complete
10Can we fill the gaps with Predictive Models?
• Complete the matrix with predicted values
• Can be used as:
• A surrogate when experimental data is not available
• A biological fingerprint
Targets
Compounds
Quantitative Structure-Activity Relationship (QSAR) models
have been built on ~800 ChEMBL targets (~550 human)
Aim to integrate these predictions with ChEMBL
Key: (Measured Data) (Predicted)
active, inactive, not tested active, inactiveQSAR Prediction Results
• Single proteins or protein complexes
• pCHEMBL values ('IC50', 'EC50', 'XC50', 'AC50', 'Ki', 'Kd', 'Potency’)
• Data from >2 articles
• >= 40 unique active and 30 inactive compounds
• Descriptors - RDKit Morgan fingerprints and physicochemical
Prediction by different methods Prediction for different target classes
Also comparing with Conformal Prediction
Includes inconclusive classification
(Norinder et al J. Chem. Inf. Model. 2014)Looking for New Compounds and Chemotypes
Marketed Drugs
UniChem
(synthesized ChEMBL (bioactive molecules)
molecules)
SureChEMBL (patented molecules)Expanding Chemical Space - Example: Suvorexant, an orexin receptor antagonist developed by Merck and approved by FDA in 2014 for treatment of insomnia. ChEMBL: SureChEMBL: • First mention 2010 • First mention 2008 • IC50/Ki binding to OX1R and • Mentioned in 77 patents OX2R receptors • Mentions of Orexin in the same • PK data in rat and dog patents • Anti-insomnic data in animal • 133 compounds >=80% similarity models • 36 compounds >-80% similarity
Orexin 1 Example: 3 Ring Scaffolds
ChEMBL
90 scaffolds
bioactivity data
for Orexin1
SureChEMBL
465 scaffolds
in patents
mentioning Orexin 1
15Can we go a Step Further?
• Suvorexant is in 19 of the UniChem indexed databases
(including ChEMBL and SureChEMBL)
• Can we search for similar compounds in UniChem?
• Work in progress ….
Structure
Standardized
UniChem InChIs Structures searchable
structures database
Un
iCh
em
Loo
ku
p
Similarity
Compounds
matching SSS
search
Similar compounds (>=80%) to Suvorexant
36 in ChEMBL,133 SureChEMBL,643 in UniChemChEMBL Users – Drug Discovery Use Cases
J Med Chem 2018 PLOS ONE 2014
“we also mine the open access
databases ChEMBL and PDB for “application of the prediction model
fragments showing PDE inhibitory on external test set composed of
activity, as well as SureChEMBL for more than 160 hH4R antagonists
recent PDE related patents, to picked from the ChEMBL database
provide a wider context for gave enrichment factor of 16.4”
exploring fragment diversity.“
J Med Chem 2017
J Med Chem 2013
“we analyzed structures of the D2/5-
HT2A ligands available in the ChEMBL
“To validate the ICM VLS models, a database (Ki < 10 nM for both receptors)
small set of 100 known KOR ligands and identified the arylamine moieties that
from the ChEMBL database were mixed could bind in the cavity between TMHs
with a decoy set of 900 compounds and 4−6, which had been identified as a
docked into all three receptor models.” tolerant region for chemical expansion”Does it get to the Site of Action and is it Safe?
ChEMBL ADME and toxicity data sources
• Scientific Literature
• Prescribing Information
• Toxicity Studies
Side effects
Therapeutic effect
No effectDoes it get there? ChEMBL PK and PPB Data
Metabolic routes
Other disposition relevant data
• Solubility
• Permeability
• Intrinsic clearanceHow CHEMBL ADME data is being used
Reasons for Compound Failure Data from: “An analysis of the attrition of drug candidates from four major pharmaceutical companies” M Waring et al, NRDD 2015 21
Is it Safe? - Challenges for Safety Prediction
• Lack of compound interaction data for many targets
relevant to toxicity
• In-vivo toxicity
• Wide datasets - A different type of “big data”
• Multiple measured endpoints
• Time and concentration effects – “everything is toxic”
• Fewer compounds = lack of chemical diversity
• Much data is on well annotated marketed drugs
• Missing exposure and tox data on the same
compounds
• Combining data in an easy to use format
22 Pre-competitive initiatives are helpingBiological Fingerprints to Predict Toxicity
Experimental Data and Model Biological Fingerprints Predict Toxicity
Predictions as descriptors Endpoint
Toxicol. Res., 2016 Combined chemical descriptors,
protein target descriptors and
cytotoxicity data to predict organ
toxicity
Chem. Res. Toxicol. 2011
Combined chemical descriptors
and gene expression data to
predict hepatotoxicity
Need more data, more curation and use of ontologies to link complex dataLearning from Existing drugs - What Works?
ChEMBL Drug & Clinical Candidate Annotation
Which target is responsible for the therapeutic effect of the drug?
Which disease is the drug used to treat?
Brivaracetam
Reasons for Drug WithdrawalFor the Future …
• 5 of the 10 top selling drugs are
currently mAbs
• Should we be gathering bioactivity data
on biologics?
Types of Drugs and
Clinical CandidatesSummary
Hit Lead
Target identification Pre-Clinical Clinical
Identification Optimisation
• Target Identification (What to work on?)
• Target to Disease links - Open Targets
• Hit identification/Lead Optimisation (Which compound?)
• Bioactivity Data - ChEMBL, SureChEMBL, UniChem
• Pre-clinical data (Is it safe, does it get there?)
• in-vivo exposure and toxicity data - ChEMBL
• Clinical Candidates & Approved Drugs (What works?)
• Efficacy target, disease annotation - ChEMBL
26Acknowledgements
EMBL-EBI Chemogenomics Team
• Andrew Leach • Eloy Felix
• Anne Hersey • Juan Mosquera
• Anna Gaulton • Francis Atkinson
• Jon Chambers • Nicolas Bosc
• Patricia Bento • Fiona Hunter
• Prudence Mutowo • Chris Radoux
• Paula Magarinos • Marleen de Veij
• David Mendez • Aldo SeguraYou can also read
