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EUGM 2013 - Ian Berry, Bob Marmon (Evotec): Classification and analysis of 21 million commercially available compounds
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EUGM 2013 - Ian Berry, Bob Marmon (Evotec): Classification and analysis of 21 million commercially available compounds

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We will discuss how we classified and calculated properties for over 21 million commercially available compounds using a variety of ChemAxon and in-house tools (and aggregated properties). We will …

We will discuss how we classified and calculated properties for over 21 million commercially available compounds using a variety of ChemAxon and in-house tools (and aggregated properties). We will show a summary of the analysis of the data and show how we will use that to build better virtual screens.

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  • 1. Building innovativedrug discovery alliancesClassification and analysis of 22 millioncommercially available compoundsChemAxon EUGM May 2013
  • 2. PAGEAgenda About Evotec About EVOsource Calculating Properties Analysis of the data Final Thoughts1
  • 3. PAGE 1) Manfred Eigen (*1927), German biophysical chemist and one of the worldwide leading pioneers in biotechnology. In 1967, he won the Nobel Prize in Chemistry for hiswork on a special measuring method of fast chemical reactions, which, until then, were considered to be immeasurable. He initiated the foundation of Evotec AG.A global company with a complete offeringEvotec worldwide operationsSales representation (Boston, Tokyo)Operations & sales representation2San Francisco,US~30 employees CompoundProcurement Compound QCand storageAbingdon,UK~215 employees Med Chem Comp Chem DMPK Structural biologyMunich,Germany~30 employees Phospho-proteomics ChemicalproteomicsGöttingen, Germany~50 employees Metabolics RegenerativeMedicineThane,India~130 employees Library synthesis &mgmt. DevelopmentchemistryHamburg,Germany~200 employees Screening HTS,NMR in vitro & in vivobiologyManfred Eigen1) Campus
  • 4. PAGEAgenda About Evotec About EVOsource Calculating Properties Analysis of the data Final thoughts3
  • 5. PAGEEVOsource4Compound Sourcing Multiple search terms Single or combinationCategory Count Suppliers 218 Catalogues 539 UniqueCompounds22156696 Parts 92490159
  • 6. PAGEEVOsource5Compound selection Can order from stores Can see if ordered Can order from supplier Can request a quote Can see if available in anotherlab (or site) Additional information displayed JChem Cartridge accessedthrough Java Persistence API Marvin Applet Structure to Name Standardizer
  • 7. PAGEThe challenges of loading supplier cataloguesIntegrated Cyclic ProcessProcessContactReceivePrepareLoad Receive catalogues– New catalogues– Catalogue updates Prepare catalogues– Convert to SD file– Structure Checker– Structure to Name– Name to Structure Contact Suppliers– Existing suppliers– Preferred suppliers– New suppliers Process– Fix errors– Expire old data Load catalogue data– Multiple parallelprocesses6
  • 8. PAGEAgenda About Evotec About EVOsource Calculating Properties Analysis of the data Final Thoughts7
  • 9. PAGEDrug likeness categoriesClassification of compoundsFeature count is defined as: # of 5- and 6-membered aromatic rings + # of Lipinski acceptors + # of Lipinski donorsDrug likeNo SS failsLipinski fails ≤ 1Additional propertyconstraints:MOE LogP ≤ 6MW ≤ 600Rot bonds ≤ 10EVO LogS ≥ -7TPSA ≤ 180AmberNo red SS failsLipinski fails ≤ 1orNo SS failsLipinski fails ≤ 2RedEverything else!Lead likeNo SS failsNo Lipinski failsAdditional propertyconstraints:MOE LogP ≤ 3.5MW ≤ 350Rot bonds ≤ 6EVO LogS ≥ -5TPSA ≤ 140FragmentsNo SS failsNo FSS failsLip. donors 1-3Lip. acc. 0-4MOE LogP ≤ 3.0MW 150-350Rot bonds ≤ 5EVO LogS ≥ -3TPSA ≤ 70Feature count 4-78
  • 10. PAGEProperty calculationsHistorical processHistorical processExport all structurescalculate properties using MOEStructural alerts using MOEStored in a MOE databaseProblemsOnly available to Comp Chem GroupDifficult to update and time consumingDifferent values using different tools – chemists use ChemAxon toolsto calculate properties9
  • 11. PAGEProperty calculationsNew process stage 1 Calculate simple properties Use ChemAxon JChem cartridge calculations where available Weekly job that calculates properties for new structures LogS uses MOE to calculate LogS manually updated every 2 months10
  • 12. PAGECalculated ResultsBreakdown of chemical space by simple descriptorsMW HBDHBAlogP RotB11
  • 13. PAGEMOE SMARTS converted to ChemAxon formatStructural alerts using two types of filter 121 SMARTS Structural Alerts – general screening compounds 19 SMARTS Fragment filters – fragment screeningAssign compounds to category – fragment, lead likeetc.Problems Took 6 months to calculate substructure search as had to be broken intosmall chunks MOE SMARTS not automatically converted to ChemAxon formatProperty calculationsNew process stage 212
  • 14. PAGEQuantitative Estimate of Drug-likeness (QED)New process stage 3Quantifying the chemical beauty of drugs, A. L. Hopkins et al, Nature Chemistry 2012, 4, 90–9813 QED calculation is based on similar parameters used to assign compounds to the Evoteccategories, each parameter is weighted from a model fitting A proof of concept was carried out on a subset of our screening collection Literature weights were modified with a bias in favour of structural alerts LogD was substituted for ALogP to consider ionisation QED calculation runs as a weekly jobWeighted QEDRelativefrequency0.49 0.67
  • 15. PAGEWhat is a beautiful molecule?Evotec weighted QED14QED = mediumQED = highQED = low
  • 16. PAGEAgenda About Evotec About EVOsource Calculating Properties Analysis of the data Final Thoughts15
  • 17. PAGEEVOsource composition16EVOsource compositionfor Evotec drug-likeness classesWeighted QEDRelativefrequency15.3%2.9M26.9%5.3M57.8%11.1M0.49 0.67EVOsource compositionfor QED indexLead-like 3.1MFragment-like 1MRed 2.1MAmber 4.2MDrug-like 8.1M
  • 18. PAGEExcellent agreement of QED and Evotec flags todiscriminate between different drug-like classes170.670.49RelativefrequencyWeighted QEDQED index profile of each Evotec drug-likeness class
  • 19. PAGEEVOsource QED distribution shows largeoverlap with orally available drugs180.670.49Weighted QEDRelativefrequencyOrally available(682 analyzed out of 770)EVOsourceOrally available drugsEVOSource
  • 20. PAGEAgenda About Evotec About EVOsource Calculating Properties Analysis of the data Final Thoughts19
  • 21. PAGEFinal thoughts and Acknowledgements EVOsource provides: A useful tool for our chemists in ordering compounds for our clients A tool for our Computational Chemists to do analyses of chemical space to better support our clients inlibrary design QED calculation is providing a useful tool for filtering data to quickly make virtuallibraries QED has been added to latest version of ChEMBL20Thanks to:Dr Oliver BarkerDr Mirco MeniconiCatherine ReisserDr Dan Warner
  • 22. Your contact:Building innovativedrug discovery alliancesIan Berry Bob MarmonManager, Informatics Senior Applications Developer+44.(0).1235.441451 Office +44.(0).1235.441402 Office+44.(0) 7802.438044 Mobile +44.(0).1235.861561 Switchboard+44.(0).1235.441503 Fax +44.(0).1235.441503 Faxian.berry@evotec.com bob.marmon@evotec.com