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www.guidetopharmacology.org
Will the real targets please stand up ?
Chris Southan
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. [email protected]
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Outline
• Target considerations• Comparing lists• Our approaches to mapping• UniProt intersects and Genome Ontology (GO) slices• Atorvastatin examples• The GToPdb GO distribution• Conclusions
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Target basics
• The most important thing for a drug is clinical proof of efficacy• However, a data-supported molecular mechanism of action
(mmoa) has crucial (bio and chem) informatics utility• The concept of primary drug target is familiar in the form of
postulating a necessary, sufficient and causal link between a direct, specific mmoa and efficacy
• Polypharmacology (multiple efficacy targets) is real but difficult to prove experimentally or clinically
• As an example, while all statins “target” HMGCR, their in vitro kinetic parameters and cross-reactivity are different and experimentally variable
• Experimental verification of target engagement in vivo is rare • In trials that can detect it, different statins have a different
clinical profiles
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Triaging activity data: PubChemBioassay for atorvastatin
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Target lists can be large and divergent
• Download: DrugBank 4.0 (May 2014), approved drugs, known pharmacological action, UniProt target identifiers
• 806 rows > 771 mapped in UniProt, 743 Swiss-Prot and 28 TrEMBL (4 human including A9UF02 BCR/ABL, 1644 aa)
• Of the 771, 622 were human Swiss-Prot• Estimate this is at least 2X the primary targets for small-
molecule drugs • Can get lists from other bioactive chemistry databases such
as Therapeutic Target Database and ChEMBL• Range of published lists available (see our website)
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Hosted target listshttp://www.guidetopharmacology.org/lists.jsp
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The GToPdb approach to target mapping
• Focus on minimal, rather than maximal relationship capture, to produce a more concise “drugged genome”
• Stringent primary activity mapping by citable results (e.g. Kd, Ki, IC50)
• Read the papers to resolve the results• Mask nutraceuticals/metabolites from drug interaction space• Use consensus target (UniProt IDs) as curation starting points• Use consensus drug structures (PubChem CIDs) as curation
starting points• Minimise complex subunit mapping to direct interactions• Don’t use matrix screen results for primary mappings• Human targets only (currently), mostly small molecules plus Abs• Pragmatic flexibility i.e. can include multi-mapping, dual
inhibitors, proven polypharmacology and unknown mmoas
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The primary target concept
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=summary&ligandId=2949
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Primary target in a complex : gamma secretase
PSEN1
http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2402
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UniProt slice ‘n dice to compare target sets
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UniProt Venn diagram between major target sources
From an approximately comparable study (on the right) the intersect has only expanded by two proteins in a year
http://www.ncbi.nlm.nih.gov/pubmed/24533037
2014
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Gene Ontology in the intersect and differentials
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Atorvastatin: mapped to different targets in 4 dbs
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Atorvastatin vs DPPIV
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Current GToPdb content
281 primary targets of approved drugs501 protein mappings of approved drugs
354 UniProt intersect
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Conclusions
• There are many reasons why drug target lists are discordant
• It is thus useful to have many to compare and discern a consensus (i.e. getting the real ones to stand up)
• At GToPdb we use consensuses as starting points to activity-map a minimal set of targets
• Utility of maximal sets include possible polypharmacology and genetic associations
• Utility of minimal sets include defining basic mmoas, a core drugged genome, a pocketome , defining data gaps, and as “small (but perfectly formed) data” to underpin “big (noisy) data”
• First-in class expansions of the minimal set are perilously low
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Acknowledgments and
references
Post-conference note: Organisations wishing to integrate GToPdb records are welcome to contact us
