acs talk open source drug discovery

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  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • acs talk open source drug discovery

    1. 1. Collaborative Drug Discovery: A Platform For Transforming Neglected Disease R&D and Beyond Sean Ekins Collaborative Drug Discovery, Burlingame, CA. Collaborations in Chemistry, Jenkintown, PA. Department of Pharmacology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ. School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD.
    2. 2. www.collaborativedrug.com In the long history of human kind (and animal kind, too) those who have learned to collaborate and improvise most effectively have prevailed. Charles Darwin
    3. 3. What does "Collaboration" mean to you? www.collaborativedrug.com Michael Pollastri • collaboration, to me, means that folks from disparate disciplines or skills work together towards the same end-goal. … A collaboration means free and open data sharing, transparent goals and intentions, and a relationship that allows open (frank) and constructive discussion. Markus Sitzmann • The internet is the perfect place to share (certain) data and many of the new technologies and format available at the Web (REST, SOAP etc.) are perfect to use data collaboratively. Jun Y. • .. some people would feel comfortable to share their ideas after some literature search or primary research. If so, is it a good practice for collaboration?
    4. 4. Why collaboration is important www.collaborativedrug.com
    5. 5. How do you store / share data <ul><li>Lab notebook - paper Old </li></ul><ul><li>Word/excel/ powerpoint other </li></ul><ul><li>Lab notebook – electronic </li></ul><ul><li>Sharepoint etc </li></ul><ul><li>Web-based database </li></ul><ul><li>Wiki / Open lab notebook Young </li></ul>www.collaborativedrug.com
    6. 6. Typical Lab: The Data Explosion Problem & Collaborations DDT Feb 2009
    7. 7. www.collaborativedrug.com
    8. 8. CDD Background <ul><li>A private company, founded in 2004 (Spun out of Eli Lilly). </li></ul><ul><ul><li>$1.89M Tuberculosis B&MGF Project </li></ul></ul><ul><ul><li>>6 Years CDD SaaS in the Cloud </li></ul></ul><ul><ul><li>Thousands of scientists engaged: </li></ul></ul><ul><li>SAB: </li></ul><ul><ul><li>Christopher Lipinski, PhD (ex Pfizer) </li></ul></ul><ul><ul><li>James McKerrow, MD PhD </li></ul></ul><ul><ul><li>David Roos, PhD </li></ul></ul><ul><ul><li>Adam Renslo, PhD </li></ul></ul><ul><ul><li>Wes Van Voorhis, MD PhD </li></ul></ul><ul><ul><li>Jim Wikel (ex Eli Lilly) </li></ul></ul>www.collaborativedrug.com
    9. 9. CDD Platform <ul><ul><li>CDD Vault – Secure web-based place for private data – private by default </li></ul></ul><ul><ul><li>CDD Collaborate – Selectively share subsets of data </li></ul></ul><ul><ul><li>CDD Public – public data sets - Over 3 Million compounds, with molecular properties, similarity and substructure searching, data plotting etc </li></ul></ul><ul><ul><ul><li>will host datasets from companies, foundations etc </li></ul></ul></ul><ul><ul><ul><li>vendor libraries (Asinex, TimTec, ChemBridge) </li></ul></ul></ul><ul><ul><li>Unique to CDD – simultaneously query your private data, collaborators’ data, & public data, Easy GUI </li></ul></ul>www.collaborativedrug.com
    10. 10. CDD3.0: Single Click to Key Functionality Copyright © 2009 All Rights Reserved Collaborative Drug Discovery
    11. 11. Collaborate Mode 1 with single login to multiple groups Consolidated CDD DB Collaborator 1 Collaborator 2 Collaborator 4 Collaborator 3 www.collaborativedrug.com
    12. 12. Collaborate Mode 2 – p2p Individual Labs securely sharing data subsets CDD DB group 1 CDD DB group 2 CDD DB group 3 CDD DB group 4 www.collaborativedrug.com
    13. 13. <ul><li>Funded by Bill & Melinda Gates Foundation for 2 years Nov 2008- Oct 2010 </li></ul><ul><li>Provide CDD software to Pilot groups and train them to use to store data </li></ul><ul><li>Provide custom cheminformatics support to pilot groups </li></ul><ul><li>Accelerate the discovery of new therapies and Advance clinical candidates through pipeline </li></ul><ul><li>Capture TB Literature and make accessible </li></ul><ul><li>CDD TB is freely available to any groups doing TB research (minimal support from CDD) </li></ul><ul><li>Integrate academic, non-profit, and corporate laboratories distributed across the globe </li></ul>CDD TB Project www.collaborativedrug.com
    14. 14. <ul><li>Tuberculosis Kills 1.6-1.7m/yr (~1 every 8 seconds) </li></ul><ul><li>1/3 rd of worlds population infected!!!! </li></ul><ul><li>Multi drug resistance in 4.3% of cases </li></ul><ul><li>extensively drug resistant increasing incidence </li></ul><ul><li>No new drugs in over 40 yrs </li></ul><ul><li>Drug-drug interactions and Co-morbidity with HIV </li></ul><ul><li>Collaboration between groups is rare </li></ul><ul><li>These groups may work on existing or new targets </li></ul><ul><li>Use of computational methods with TB is rare </li></ul><ul><li>Literature TB data is not well collated (SAR) </li></ul>Building a disease community for TB www.collaborativedrug.com
    15. 15. The Long Tail and CDD Collated for each user the number of data uploads–de-identified Rank-frequency plot of contributions to CDD. Solid line: power law with alpha = 2.2; dashed line, alpha =2.7. (20% contribute 80%) suggests a power law with a considerable downward tail which is a signature of &quot;saturation&quot; of the audience, i.e. in a fixed universe of users, a majority of possible people are becoming active contributors. Robin Spencer in Ekins et al, Book chapter 2010
    16. 16. 15 public datasets for TB >300,000 cpds Patents, Papers Annotated by CDD Open to browse by anyone http://www.collaborativedrug.com/register Molecules with activity against
    17. 17. <ul><li>Biomolecules essential for survival and growth are essential molecules. </li></ul><ul><li>in vivo mutagenesis of the M. tuberculosis genome and generated, archived and genotyped 5,126 mutants. </li></ul><ul><li>Statistical analysis to determine putative essential genes. </li></ul><ul><li>Essential molecules classified as the products of enzymes that are encoded by genes in this list </li></ul><ul><li>Similarity searches with essential molecules in CDD using ChemAxon tools </li></ul><ul><li>e.g. bleomycin has 57% molecular similarity to UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelyl-D-alanyl-D-alanine, </li></ul><ul><li>MIC of 0.1 µg/ml. – </li></ul><ul><li>guinea pigs treated with bleomycin had smaller lesions, fewer acid-fast bacilli and a prolonged survival time. </li></ul>Searching for molecular mimics Freundlich et al., Pub # 258 Tues Aug 24 – 5.30-7.30pm Hall C
    18. 18. biomolecules essential for metabolism and survival of Mtb and their structural analogs Freundlich et al., Pub # 258 Tues Aug 24 – 5.30-7.30pm Hall C
    19. 19. Simple descriptor analysis 4.72 (1.99) 77.75 (30.17)** 42.43 (8.94)* 0.12 (0.34)** 4.24 (1.58) 1.11 (0.82)** 3.38 (1.36)** 352.59 (70.87) Inactive < 90% inhibition at 10uM (N =100,931) 4.76 (1.99) 70.28 (29.55) 41.88 (9.44) 0.19 (0.40) 4.18 (1.66) 0.98 (0.84) 4.04 (1.02) 349.58 (63.82) Active ≥ 90% inhibition at 10uM (N =1702) TAACF-NIAID CB2 4.91 (2.35) 85.06 (32.08)* 43.38 (10.73) 0.09 (0.31)** 4.86 (1.77) 1.14 (0.88) 2.82 (1.44)** 350.15 (77.98)** Inactive < 90% inhibition at 10uM (N = 216367) 4.85 (2.43) 83.46 (34.31) 42.99 (12.70) 0.20 (0.48) 4.89 (1.94) 1.16 (0.93) 3.58 (1.39) 357.10 (84.70) Active ≥ 90% inhibition at 10uM (N = 4096) MLSMR RBN PSA Atom count RO 5 HBA HBD logP MWT Dataset
    20. 20. Bayesian Classification Screen Good Bad active compounds with MIC < 5uM Laplacian-corrected Bayesian classifier models were generated using FCFP-6 and simple descriptors. 2 models 220,000 and >2000 compounds Ekins et al., Mol BioSyst, 6: 840-851, 2010 www.collaborativedrug.com
    21. 21. Bayesian Classification Dose response Good Bad Ekins et al., Mol BioSyst, 6: 840-851, 2010 www.collaborativedrug.com
    22. 22. Bayesian Classification Leave out 50% x 100 Ekins et al., Mol BioSyst, 6: 840-851, 2010 www.collaborativedrug.com 65.47 ± 7.96 67.21 ± 7.05 66.85 ± 4.06 0.75 ± 0.01 0.73 ± 0.01 MLSMR dose response set (N = 2273) 77.13 ± 2.26 78.59 ± 1.94 78.56 ± 1.86 0.86 ± 0 0.86 ± 0 MLSMR All single point screen (N = 220463) Sensitivity Specificity Concordance Internal ROC Score External ROC Score Dateset (number of molecules)
    23. 23. >10 fold Enrichment with TB Bayesian model Filtering a further 100K compound library Ekins et al., Mol BioSyst, In Press www.collaborativedrug.com 82 (4.82) 107 (6.29) 9.95 (0.58) 600 70 (4.11) 92 (5.41) 8.29 (0.49) 500 58 (3.41) 77 (4.52) 6.63 (0.39) 400 54 (3.17) 64 (3.76) 4.98 (0.29) 300 42 (2.47) 48 (2.82) 3.32 (0.19) 200 24 (1.41) 23 (1.35) 1.66 (0.10) 100 0 0 0 0 dose response Bayesian model (%) single point screening (200k) Bayesian model (%) Random hit rate (%) Number of compounds screened
    24. 24. GSK data– Malaria hits Gamo et al., Nature , 2010, 465 , 305-310
    25. 25. Press
    26. 26. <ul><li>What are the challenges and opportunities for the field? </li></ul><ul><li>How are your priorities changing? </li></ul><ul><li>What are the emerging bottlenecks? </li></ul><ul><li>What if? </li></ul><ul><ul><li>Any technology, any collaborators, if you had a magic wand… </li></ul></ul>Register for GlaxoSmithKline on CDD Public http://www.collaborativedrug.com/register
    27. 27. GSK vs St Jude vs Novartis antimalarial datasets. Ekins and Williams Drug Disc Today In Press Ekins and Williams submitted (2010) a screening hits in total are not ‘lead-like’ (MW < 350, LogP< 3) closest to ‘natural product lead-like’. Although GSK suggests that the compounds are “drug-like” the evidence for this is weak 5.8 ± 3.0 53.4 ± 21.2 0.2 ± 0.6 5.3 ± 1.5 1.8 ± 1.0 3.8 ± 1.6 341.6 ± 67.0 Antimalarial drugs (N = 14) 7.1 ± 7.7 90.6 ± 104.4 0.6 ± 0.9 5.4 ± 4.7 2.1 ± 3.4 2.2 ± 2.7 458.0 ± 298.6 Johns Hopkins Subset > 50% malaria inhibition at 96h (N = 165) 5.4 ± 9.6 96.0 ±139.8 0.3 ± 0.8 5.1 ± 5.5 2.4 ± 4.6 1.2 ± 3.4 349.1 ± 355.8 Johns Hopkins All FDA drugs (N = 2615) 5.6 ± 3.0 74.7 ± 37.9 0.4 ± 0.7 4.7 ± 2.1 1.2 ± 1.1 3.7 ± 2.0 398.2 ± 105.3 Novartis (N = 5695) 5.2 ±2.3 72.2 ±29.3 0.2 ± 0.4 4.9 ± 1.8 1.1 ± 0.8 3.8 ± 1.6 385.3 ± 71.2 St Jude (N = 1524) 7.2 ± 3.4 76.8 ± 30.0 0.8 ± 0.8 5.6 ± 2.0 1.8 ± 1.0 4.5 ± 1.6 478.2 ± 114.3 GSK data (N = 13,471) RBN PSA (Å 2 ) Lipinski rule of 5 alerts HBA HBD logP MW Dataset
    28. 28. Mtb Compound libraries and filter failures Filtering using SMARTs filters to remove thiol reactives, false positives etc at University of New Mexico (http://pasilla.health.unm.edu/tomcat/biocomp/smartsfilter) Ekins et al., Mol BioSystems In press www.collaborativedrug.com
    29. 29. Antimalarial Compound libraries and filter failures Ekins and Williams., submitted (2010) b www.collaborativedrug.com % Failure
    30. 30. The future: Alerts in CDD
    31. 31. Summary Active compounds vs Mtb and P. Falciparum have higher mean molecular weights and logP values A high proportion of compounds that fail the Abbott filters for reactivity when compared to drugs and antimalarials Understanding the chemical properties and characteristics of compounds = better compounds for lead optimization. St Jude and Novartis datasets should be screened vs Mtb as their property space is close to TB actives GSK compounds may not be an ideal starting point for lead optimization for malaria
    32. 32. Systems biology Pathways analysis Data bases Docking model Commercial/ combinatorial/ corporate library HTS following reactivity rules and property filtering Hit to lead -efficacy vs. target, -whole-cell, -infected organism Pharmacophore, QSAR, ADME filters, target fishing Docking/Virtual screening, and/or structure based methods Phenotypic screening Target-based screening Use phenotypic data with integrated computational methods to suggest potential target/s and optimize ADME properties in parallel, then verify in vitro For chemical probe selection find new compounds that inhibit a target using tightly integrated computational methods then optimize and feedback data to data bases and pathways Hit to lead -efficacy vs. target, -whole-cell, -infected organism Follow up virtual screening Follow up virtual filtering/screening When target identified could pursue target based screening workflow Ekins et al, submitted 2010 c Pharmacophore, QSAR, ADME filters TB screening molecule data base TB screening molecule data base
    33. 33. The future: crowdsourced drug discovery <ul><li>Growth in open and public resources (software + data + models) </li></ul><ul><li>Precompetitive data and tools – e.g. Pistoia Alliance, Innovative medicines initiative </li></ul><ul><li>Academic - Industry Collaborations, NM4TB, etc </li></ul><ul><li>Open innovation, need to capture non-published data </li></ul><ul><li>Competitive collaboration </li></ul><ul><li>Risks: </li></ul><ul><li>-quality of data curation, new visualization and modeling tools </li></ul><ul><li>gap between growth in databases and new tools </li></ul><ul><li>Compound accessibility / availability will be bottleneck – testing in silico hypotheses </li></ul><ul><li>Engage pharmas – (Gupta et al., Pub # 405, Wed 7-9pm Ballroom) </li></ul>Williams et al Drug Discovery World, Winter 2009 Ekins S. and Williams AJ, Pharm Res, 27: 393-395 (2010) Ekins S and Williams AJ, Lab On A Chip, 10: 13-22, 2010. Bingham A and Ekins S, Drug Disc Today, 14, 1079-1081, 2009.
    34. 34. Possessed by a single person, [the process] would remain stationary for a long time, and perhaps would die away; but being made public, it will thrive and improve through the efforts of all. Joseph Louis Gay-Lussac 1839
    35. 35. Acknowledgments <ul><li>Antony Williams (RSC) </li></ul><ul><li>Joel Freundlich, (Texas A&M) </li></ul><ul><li>Gyanu Lamichhane, Bill Bishai (Johns Hopkins) </li></ul><ul><li>Jeremy Yang (UNM) </li></ul><ul><li>Nicko Goncharoff (SureChem) </li></ul><ul><li>Chris Lipinski </li></ul><ul><li>Takushi Kaneko (TB Alliance) </li></ul><ul><li>Bob Reynolds (SRI) </li></ul><ul><li>Carolyn Talcott and Malabika Sarker (SRI International) </li></ul><ul><li>Robin Spencer (http://scaledinnovation.com/) </li></ul><ul><li>GSK </li></ul><ul><li>Accelrys </li></ul><ul><li>Bill and Melinda Gates Foundation </li></ul>ekinssean@yahoo.com ; [email_address]
    36. 36. PAPERS Rishi R. Gupta, Gifford, EM, Liston T, Waller CL, Hohman M, Bunin BA and Ekins S, Using open source computational tools for predicting human metabolic stability and additional ADME/Tox properties, Drug Metab Dispos, In Press 2010. Ekins S and Williams EJ, When Pharmaceutical Companies Publish Large Datasets: An Abundance of riches or fool’s gold, Drug Disc Today, In Press 2010. Ekins S, Gupta R, Gifford E, Bunin BA, Waller CL, Chemical Space: missing pieces in cheminformatics, Pharm Res, In Press 2010. Ekins S. and Williams AJ, Reaching out to collaborators: crowdsourcing for pharmaceutical research, Pharm Res, 27: 393-395, 2010. Ekins S and Williams AJ, Precompetitive Preclinical ADME/Tox Data: Set It Free on The Web to Facilitate Computational Model Building to Assist Drug Development. Lab On A Chip, 10: 13-22, 2010. Ekins S, Bradford J, Dole K, Spektor A, Gregory K, Blondeau D, Hohman M and Bunin BA, A Collaborative Database and Computational Models for Tuberculosis Drug Discovery, Mol BioSyst, 6: 840-851, 2010. Williams AJ, Tkachenko V, Lipinski C, Tropsha A and Ekins S, Free online resources enabling crowdsourced drug discovery, Drug Discovery World, Winter 2009. Louise-May S, Bunin B and Ekins S, Towards integrated web-based tools in drug discovery, Touch Briefings - Drug Discovery, 6: 17-21, 2009. Hohman M, Gregory K, Chibale K, Smith PJ, Ekins S and Bunin B, Novel web-based tools combining chemistry informatics, biology and social networks for drug discovery, Drug Disc Today, 14: 261-270, 2009.
    37. 37. CDD is Secure & Simple <ul><li>Web based database (log in securely into your account from any computer using any common browser – Firefox, IE, Safari) </li></ul><ul><li>Hosted on remote server (lower cost) dual-Xeon, 4GB RAM server with a RAID-5 SCSI hard drive array with one online spare </li></ul><ul><li>Highly secure, all traffic encrypted, server in a secure professionally hosted environment </li></ul><ul><li>Automatically backed up nightly </li></ul><ul><li>MySQL database </li></ul><ul><li>Uses JChemBase software with Rails via a Ruby-Java bridge, (structure searching and inserting/ modifying structures) </li></ul><ul><li>Marvin applet for structure editing </li></ul><ul><li>Export all data to Excel with SMILES, SDF, SAR, & png images </li></ul>www.collaborativedrug.com

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