5. Library Enhancement Strategy … analyze existing collection Collaborative Services Corporate Screening Collection Desired Compounds Acceptable Compounds Unacceptable Compounds Poor Chemistry Undesirable Properties Discard Good Chemistry Drug-like Properties Screen Good Chemistry Lead-like Properties Buy Compounds can be further subdivided by target
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9. Synthesis of Enhancement libraries … Sources of Scaffolds From “Ideas” Database (~2500 ideas) From Chemists “chemical intuition” From “de novo” Scaffold Generation Scaffolds should be vetted for applicability Scaffold Idea Representative subset of reagents “ mini” virtual library Check that library has reasonable property profile and no overlap with known compounds For targeted libraries, use docking or similarity scores to verify desirability of the potential library Shape-based hierarchical clustering is employed to select diverse scaffolds 27,417 meet “rule of 5” 14,322 meet “rule of 4.5” 3,918 meet “rule of 4” using Aldrich reagents ClogP MW Collaborative Services
10. Careful Reagent Selection … enhance synthetic success Reagent Pool Vendor Catalogs Library Reagents Depending on the library design goals, custom synthesized and novel in-house reagents may also be used Reaction-Compatible Reagents must be compatible with reaction conditions in current and following reaction steps Reagant-Compatible Reagents must not contain competing functional groups Drug-like Cannot contain known toxicophores, etc. Reasonable Available at reasonable cost Collaborative Services
11. Type of Library Needed Depends on What is Known Lead Optimization Hit Validation or Lead Finding Hit Finding Knowledge of Target Protein X-ray Pharma- cophore Protein Class None Structure Based Design Pharmacophore Based Design Focused Sets Diverse Libraries Need for diversity is inversely proportional to knowledge about the target Degree of Diversity Needed and where you are in the drug-development process Collaborative Services Oprea, Ed. ChemoInformatics in Drug Discovery, Wiley, 2005, p. 45
12. Focused libraries are rapidly generated by combining high quality sources of library ideas with techniques for filtering these ideas using knowledge of the target. The process is iterative. Each new library adds to the knowledge base. So good SAR will be built into the libraries. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Virtual Screening Ideas Database Knowledge Base Chemist Ideas de novo Design Rapid Development of Focused Libraries Collaborative Services
13. Rapid Development of Focused Libraries Ideas can come directly from the chemist or other sources, based on knowledge or intuition. The ideas database consists of reaction protocols for scaffolds, whose analogs have been made or synthetic route has good precedent, combined with sets of well vetted reagents. Our de novo tools use target and synthetic knowledge to generate relevant suggestions. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Virtual Screening Ideas Database Knowledge Base Chemist Ideas de novo Design Collaborative Services
14. Rapid Development of Focused Libraries The knowledge base is a continually evolving repository of knowledge about the desired target. Information may come from public sources, such as crystal structures or patents. Information may also come from the customer, for example, results of earlier screening programs against the target of interest. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Virtual Screening Ideas Database Knowledge Base Chemist Ideas de novo Design Collaborative Services
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16. Rapid Development of Focused Libraries The compounds that survive the virtual screening are all potentially active in the target. Generating the library design is the process of reducing this still potentially very large pool to a subset of compounds that can be synthesized, have reasonable reagent reuse, have the best potential to show activity and incorporate SAR to help understand the screening results. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Virtual Screening Ideas Database Knowledge Base Chemist Ideas de novo Design Collaborative Services
17. Rapid Development of Focused Libraries Converting a library design into a physical set of compounds to screen is an interactive process involving design and medicinal chemistry. As the synthesis proceeds and the chemistry is better understood, some reagents may not be viable. This knowledge is fed back to design, and replacements chosen to insure the final compounds retain the same level of desirability as the initial set. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Virtual Screening Ideas Database Knowledge Base Chemist Ideas de novo Design Collaborative Services
18. Initial screening results in a number of hits and neighborhood analysis can be used to differentiate true positives from false positives. IC 50 data from identified leads can be fed back into the knowledge base to identify additional libraries to synthesis. The leads can also be optimized using more refined techniques such as QSAR/CoMFA to optimize activity or pharmacological properties. Lead Molecules Synthesis Screening Library Design Computer Design Focused Library Candidate Pool Ideas Database Knowledge Base Chemist Ideas de novo Design Rapid Development of Focused Libraries Virtual Screening Collaborative Services
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21. Scaffold Selection All sources of scaffolds can benefit from analysis Process most important for scaffolds with the least prior medicinal chemistry input Representative reagents Pool of scaffolds Virtual Libraries Pool of Scaffold candidates Desired scaffold subset Appropriate physical properties Leadlike ADME/tox Appropriate match to target Efficiency and cost of design Similarity Docking Models Diversity analysis Match to target Novelty OptDesign Goal is to rank potential scaffolds on ability to produce a good pool of synthetic candidates. This can be very fast using our virtual screening technology Collaborative Services
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25. ADMET Predictions Poor BBB Permeability Good BBB Permeability Moderate BBB Permeability High bioavailability (good solubility and Permeability) Low bioavailability (poor solubility and permeability) Problematic bioavailability (poor solubility and good permeability) Problematic bioavailability (good solubility and poor permeability) Collaborative Services Delaney, J. S. J. Chem. Inf. Comput. Sci. 2004 , 44 , 1000 – 1005. ESOL – Estimated Aqueous Solubility
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27. Topomer Distances Split molecule into 2-3 fragments Rule-based alignment of fragments onto a grid Use probe atom to calculate steric potential at grid points Topomer Fields Topomer distances are the sum of the pair-wise differences between the fields summed over the fragments plus alignment and steric penalties An example result from a Tripos validation study is shown above Similarity Searching Topomer based searching is effective in searching large virtual libraries Topomer fields can also be used for CoMFA predictions in virtual libraries Collaborative Services N F O O N + H 7.6 uM Query Structure Lead Hop D4.4
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32. We know which compounds to make Design Environment Production Environment Difficult Simple Distant Close Highest interest & earliest delivery High interest & long delivery Synthesis development & Reagent synthesis Low interest & later delivery Low interest & quick delivery Every compound we make is designed and tracked via the informatics system Collaborative Services
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38. Summary Exelgen Discovery provides a broad spectrum of competitively priced Discovery Products and Services. For further information or enquiries please contact: Exelgen Discovery Bude-Stratton Business Park Bude EX23 8LY Cornwall, UK Dr Phil Billington Business Development Email: Mob: Dr Julian Smith Principal Scientist Email: Mob: Tel/Fax: +44 (0)1288 356500 [email_address] +44 07973 493403 [email_address] +44 07805 571662