Vanderwall cheminformatics Drexel Part 1

Cheminformatics & The evolving relationship between data in the public domain & pharma Dana Vanderwall Cheminformatics, Bristol-Myers Squibb

How do we start to find a new chemical that might be the next drug? ,[object Object],[object Object],[object Object],[object Object]

This is where drug discovery gets really modern ,[object Object]

Compound optimization ,[object Object],[object Object],1-3 years >2 million compounds tested in primary assay Make another 2-10,000

Getting ready for the clinic ,[object Object],[object Object],[object Object],[object Object],[object Object],1-3 years 2-3 years

Profiling Assays and Lead Op Progression 2M 2K 200 1-10 1 2-5 10-50 300-600 HTS Hit Triage Early Lead Op Late Lead Op Target to Hit Hit to Lead Lead to Candidate # Compounds # Assays

Chemical Structures are the Intellectual Property ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

GlaxoSmithKline moves to stimulate public-private partnerships for R&D in neglected tropical diseases ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Malaria ,[object Object],[object Object],[object Object],http://www.mcwhealthcare.com/malaria_drugs_medicines/life_cycle_of_plasmodium.htm

The Complexity of Cell Biology The assumption is: One target One consequence Target ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Target

Emerging paradigm- look for the cellular activity first ,[object Object],[object Object],[object Object]

Supporting black-box HTS for anti-malarials ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],F-J Gamo et al. Nature 465 , 305-310 (2010) doi:10.1038/nature09107

Characterizing the hits ,[object Object],[object Object],[object Object]

Three-dimensional plot of some of the novel chemical diversity present in TCAMS F-J Gamo et al. Nature 465 , 305-310 (2010) doi:10.1038/nature09107

Characterizing the hits ,[object Object],[object Object],[object Object],[object Object]

Can we leverage the historical target data on compounds? ,[object Object],[object Object],Can we use the data to figure out which targets lead to which biological response? ? stimulant readout ,[object Object],[object Object],kinase_1 kinase_2 kinase_3 kinase_4 7TM_1 7TM_2 NR_3 NR_2 NR_1

Can we leverage the historical target data on compounds? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Finding targets ‘enriched’ among the anti-malarials ,[object Object],[object Object],[object Object]

Narrowing down the possible candidates ,[object Object],[object Object],[object Object],>2 fold enrichment F-J Gamo et al. Nature 465 , 305-310 (2010) doi:10.1038/nature09107

Targets with homologues in P. falciparum genome Aspartic protease Methionyl-tRNA synthetase b-Ketoacid reductase Phenylalanyl-tRNA synthetase Calcium/calmodulin-dependent kinase Phosphatidylinositol 3-kinase Cysteine protease Plasmodium electron transport chain Dihydrofolate reductase Ribosome Dihydroorotate dehydrogenase Ser/Thr protein kinase DNA gyrase Tyrosyl-tRNA synthetase Isoleucyl-tRNA synthetase

Targets with NO homologues in P. falciparum genome GPCR: Adrenergic antag Nuclear Receptor ag/antag GPCR: Cannabanoid antag Ion Channel inh GPCR: Chemokine antag Phospholipse inh GPCR: Cholinergic ag Lipid amide hydrolase inh GPCR: Free Fatty Acid ag Serine protease inh GPCR: Serotonin ag/antag Toll-like receptor ag GPCR: Opiod ag/antag GPCR: Peptide hormone receptor ag/antag

Data publicly available ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

And the raw target data used to develop hypotheses? ,[object Object],[object Object],[object Object],[object Object],[object Object]

Surrogates for internal data ,[object Object],[object Object],[object Object],[object Object]

Acknowledgements Anti-malarial HTS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Vanderwall cheminformatics Drexel Part 1

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