Presented at Centre for Integrative Systems Biology and Bioinformatics meeting at Imperial College London “Modelling Biological Systems” March 2019

1. The utility of for selecting
drugs and probes as systems biology
perturbagens
Christopher Southan
Modelling Biological Systems Symposium, Imperial College London, 26 March 20191
https://sites.google.com/view/tw2informatics/home

2. Outline
• Chemical perturbation
• PubChem content and coverage
• Targets
• Drugs
• Probes
• Looking at BAY 7598
• Getting into PubChem
• Conclusions
2

3. Advantages of chemical peuterbation of
biological systems
• Dose response, rapid onset, and time course measurement
• Reversable by washout > retest by pulsing
• Should be robustly reproducible
• Broad choice of controls (e.g. different binding sites, potencies, kinetics,
chemotypes, SAR including inactive analogues)
• In vitro and In cellulo target engagment/mechanistic validation
• Protein/Protein interaction inhibitors
• Option of multiple pathway/network intervention testing
• Omic profiling of effects (e.g. transcripts, imaging, metabolites, proteomics)
• Orthogonal hypothesis testing viaCRISPR, RNAi, KO, antibody ect
• Peptides, nucleotides, antibodies or endogenous metabolites can be tried
• Druggable genome target coverage increasing (e.g. PROTACs)
• Can use compounds with unkown mechanism (e.g. phenotypic screening hits)
• Not restricted to proteins (e.g. RNA-small molecule interactions)
• ~ 3 million bioactive compounds available in PubChem
• Analogue expansion by synthetic chemistry 3

4. TheTriumvirate:
Substance, Compound, BioAssay
4
• SIDs can be
biololecules (e.g. large
peptides and
antobodies, no images
• CIDs merge SMILES
strings < 1000 atoms,
to unique InChIs
• Average SID:CID ~ 2.6,
drugs ~50, aspirin (CID
244) 307 plus 1563
mixture SIDs
• CIDs 4.7 % mixtures

5. PubChem CID growth 2005 - 2018
5

6. CID statistics overview
( March 2019)
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7. Potential perturbagen coverage in PubChem
• 80 million rule-of-five chemical space
• 3.4 million tested > 1.25 million active in BioAssay
• 1.0 million assays > 240 million bioactivities
• Activities extracted from ~ 100K papers
• 12,000 protein targets
• ~ 8000 PDB ligands
• 12,000 with BioSytems pathway mappings
• 9500 drugs, ~ 1500 FDA approved
• BindingDB 20,500 cpds, 260 patents, 42,000 activities (just 2019)
• Activity data not in PubChem but in patents ~2.5 million
• Probes, full leads and develpment cpds unkown (not cleanly tagged)
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8. Curated sources of human targets
8
• All four are PubChem
submitting sources
for linked chemistry
• Most extracted from
publications
• They all have UniProt
cross-references
• Numbers shown are
for Human Swiss-Prot
• Represent a maximal
and consensus
druggable genome

9. Drugs vs leads vs probes vs tools: Drugs
• Approved drugs have accumulated data on systems perturbations and
molecular mechanisms of action
• However, the primary human target number is below 400 and little may
be known on secondary targets and (systems) polypharmacology
• Optimisation of ADMET drug parameters may reduce desirable
perturbagen properties such as potency, Kd in vitro and in cellulo
• However the same ADMET optimisation means they can go straight into
cells, organoids, rodents, zebrafish or other model systems
• Chemical vendor and patent SAR coverage are usefully high for drugs
• Drugs are designed for patient efficacy but not to provide systems
biology mechanistic insights per se
• Past and present development compounds (~ 15,000 +) cover a much
wider range of targets but are difficult to select cleanly in PubChem
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10. Selecting approved drugs from Guide to Pharmacology
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9526 SIDs > 1509 approved drugs > mapping to 1321 CIDs

11. Old drugs
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12. New drugs
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https://cdsouthan.blogspot.com/2019/01/2018-approved-drugs-in-pubchem.html

13. Probes, repurposing and tools
• Probes are designed to modulate a target for mechanistic and system
insights rather than therapeutic utility in first instance
• Probe guidelines published on potency, specificity and activity in cells
• Interesting differences between the NIH first generation probes circa 1990-
2010 and the later generation from SGC and others in last few years
• Repurposing compounds from AstraZeneca, Boehringer and other
companies also potentially useful as perturbagens
• Tool compound is a broader term for anything with useful specificity that
might not be strictly a drug or a probe (e.g. spider venoms against ion
channels)
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14. Useful external probe source for
”mapping in” to PubChem
14

15. Tracking a probe example into PubChem
15

16. Not so easy to get the structure
16

17. The bad news : PubChem has it from a Bayer patent
but no BioAssay data and not named as BAY 7598
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18. The good news : MMP12 is indexed in PubChem
with 7 Guide to Pharmacology curated inhibitors
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19. You too can get
into PubChem
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If your perturbation
experiments are
reproducible then put the
results into PubChem
BioAssay (to be FAIR)
https://cdsouthan.blogspot.com/2017/08/getting-into-pubchem-again.html

20. Conclusions
• As the de facto global nexus for bioactive chemistry PubChem has become
an essential resource for perturbagen choices and cross-checks
• Between drugs, development compounds, leads, probes and patent SAR
sets there is a increasingly wide chemical toolbox choice
• PubChem synergises with the stand-alone sources integrated into it such as
ChEMBL, Guide to Pharmacology, DrugBank, BindingDB and DrugCentral
• Note these may offer easier entry points but follow structures back into
PubChem for source checking, BioAssay assessment, neighbour assessment
and patent links
• UniProt offers an alternative entry point from the chemically modulatable
protein target side and their cross-reference intersecting is very powerful
• Despite their increasing importance collective indexing of probes is poor
• Like all such sources, PubChem it has navigation quirks, caveats, submitter
quality issues, gotchas and cheminformatic challenges
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21. References
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22. Further PubChem tips and tricks
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https://www.slideshare.net/cdsouthan/presentations https://cdsouthan.blogspot.com/