An Integrated Approach To Drug Discovery Using Parallel Synthesis. The history of parallel chemistry for lead discovery at Pfizer Sandwich from begining to outsourcing
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An Integrated Approach To Drug Discovery Using Parallel Synthesis
1. An integrated approach to drug discovery using parallel synthesis Graham F Smith Sandwich Chemistry Pfizer Global Research and Development
2. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS
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6. Beautiful compound concept parallel chemistry no toxicophores rule of 5 compliant pure and stable Pfizer exclusive Lipinski, C.A. Chris Lipinski Discusses Life and Chemistry after the Rule of Five. Drug Discovery Today 2003 , 8 , 12-16.
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11. File Enrichment – managing diversity La Jolla Groton Ann Arbor Sandwich Generation of ideas for library protocols Global Ideas overlap resolution La Jolla Groton Ann Arbor Sandwich Prioritization of ideas for development Library chemistry development Library idea Management Tool La Jolla Library production and purification
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13. Overview Enabled Hit Follow Up & Productive lead Discovery File Enrichment Chemo informatics High Throughput Chemistry HTS
19. Global Protocol database intranet access All Parallel Chemistry searchable in one place All 9 PGRD site use this tool All File enrichment research captured in the global database A link from compound to parallel synthesis protocol
20. Architecture based on Formal Reactions Protocols are associated into Formal Reactions VRXN-2-00001 Reductive amination as a family of protocols aldehydes nucleophilic amines Two protocols of broadest scope cover the largest range of potential ---- thus potential for re-use: Capturing these is what really builds the asset in global Chemical Knowledge Bases VRXN-2-00001 is defined by the Formal Reaction scheme and spans the space covered by all suitable amines & aldehydes in the linked inventory db
21. Formal Reactions as Families of Protocols 21 VRXN-3-00029 4 VRXN-3-00007 2 VRXN-2-00081 3 VRXN-2-00018 7 VRXN-2-00017 9 VRXN-2-00016 8 VRXN-2-00013 15 VRXN-2-00011 39 VRXN-2-00010 12 VRXN-2-00009 9 VRXN-2-00007 16 VRXN-2-00005 4 VRXN-2-00004 11 VRXN-2-00002 13 VRXN-2-00001 Source (each color represents one of the Pfizer R&D sites) # of explicit protocols within reaction family Name of Formal Reaction (broad scope rxns)
24. Access to virtual libraries from the desktop Suitable monomers retrieved for each reaction protocol Properties calculated Inventory and location searched Clustering and filtering pre and post enumeration
39. Crystal Structure of UK-411,930 bound to CDK2 - SBLD 2.3A resolution data SRS, Daresbury. Key pyrazole Donor Acceptor Donor interaction
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41. Overview of Closed-loops for IKK Activity goes up with library iteration Number of actives increases with library iteration 0 10 20 30 40 50 60 0 1 2 3 4 5&6 Closed-loop iteration % of compounds active at 10 M 1 10 100 1000 10000 activity of most potent compound (nM)