Presented at the University of Capetown on 10th of July. A shorter version "Analysing the drug targets in the human genome" was presented at the World Congress of Pharmacology on the 15th of July
Analysing targets and drugs to populate the GToP database
1. www.guidetopharmacology.org
Analysing targets and drugs to
populate the GToP database
Chris Southan, presented at the University of Capetown, July 2014
IUPHAR/BPS Guide to PHARMACOLOGY Web portal Group, Centre for Integrative Physiology,
School of Biomedical Sciences, University of Edinburgh,
Hugh Robson Building, Edinburgh, EH8 9XD, UK.
cdsouthan@hotmail.com
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2. Outline
• Target considerations
• Target numbers in databases and the literature
• The GToPdb approach to primary target mapping
• Target proteins and Gene Ontology comparisons
• The GToPdb approved target function distribution
• Drug consensus sets
• Conclusions
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3. Target considerations
• The capture (in GToPdb and other sources) of the data-supported
molecular mechanisms for a drug has crucial pharmacological,
bioinformatics and cheminformatics utility
• The concept of “primary target” postulates a causal, necessary and
sufficient link between a direct drug binding and clinical efficacy
• Polypharmacology (multiple efficacy targets) is important but difficult to
prove experimentally or clinically
• The in vitro kinetic parameters and cross-reactivity for the same
mechanisms are different and experimentally variable
• Verification of target engagement and residence time in vivo is rare
• Many proteins in listings are not actual drug targets ; (e.g. albumin,
trypsin, HERG,APP, P450s) or were not (e.g.ACE2, BACE2)
• Phenotypic screening may be on the ascendance, but deconvolution to
mechanism of action remains important
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7. The GToPdb approach to target mapping
• Focus on minimal, rather than maximal relationship capture, to produce a
concise “drugged genome”
• Read the papers to resolve the mechanisms
• Stringent mapping by citable data (e.g. Kd, Ki, IC50)
• Mask nutraceuticals/metabolites/hormones from these mappings
• Use consensus sets (human UniProt/Swiss-Prot IDs) to map “out” to drugs
• Use consensus drug structures (PubChem CIDs) to map “in” to targets
• Reduce complex subunit mapping to direct interactions
• Avoid matrix screening results for primary mappings
• Pragmatically flexible i.e. can include dual inhibitors, proven secondary
targets, non-human mappings or unknown mechanisms
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11. Intersects and differences between target sets
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Selects made from
June 2014 UniProt
(no species filter)
ChEMBL
DrugB = DrugBank
Bdb = BindingDB
GTP = Guide to
PHARMACOLOGY
15. Getting to the real drugs:
developing a consensus triage
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16. Issues for approved drug structure discordance
• Our analysis is being extended to include additional drug sources and we have
constituted a new NC-IUPHAR expert subcommittee to support us in resolving
challenging cases
• We have introduced new relationships such as drug <-> prodrug and active
metabolites
• Representational discordance between the same canonical drugs in documents
and databases is a serious issue in pharmacology, medicinal chemistry and
cheminformatics
• Contributory factors include naming inconsistencies, salt permutations, stereo
forms, tautomerism, legacy dominance of PDF images and errors
• Definitive sets will require not only more inter-source collaboration for
standardisation (including wider use of InChI) but also that regulatory bodies and
pharmaceutical companies directly engage with provenancing public database
structures for clinically used drugs
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17. Conclusions
• Published and database target numbers diverge mainly because of
different curatorial selectivity
• Current inner limit ~ 300, outer limit ~ 2000
• New mechanisms for new approved drugs are low
• GToPdb uses consensus lists as starting points for curation
• Utilities of our minimal primary target set:
– Validated mechanisms
– Defining the core drugged genome and pocketome
– Use as “small (but perfectly formed) data” to underpin “big (noisy) data”
• Drug structure discordance in global databases is a serious issue
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