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Predictive Toxicology

Predictive Toxicology. Session Chair: Curt Breneman (RPI Chemistry / RECCR Director). The World of Predictive Modeling. X. CHEMICAL/ BIOLOGICAL ACTIVITY. MOLECULAR STRUCTURE. Statistical or Pattern Recognition Methods. MOLECULAR REPRESENTATION. Structure-Activity Relationships.

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Predictive Toxicology

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  1. Predictive Toxicology Session Chair: Curt Breneman (RPI Chemistry / RECCR Director)

  2. The World of Predictive Modeling

  3. X CHEMICAL/ BIOLOGICAL ACTIVITY MOLECULAR STRUCTURE Statistical or Pattern Recognition Methods MOLECULAR REPRESENTATION Structure-Activity Relationships

  4. Cheminformatics:Models and Statistical Methods • “If your experiment needs statistics, you ought to have done a better experiment” • Ernest Rutherford “But what if you haven’t done the experiment yet?”

  5. Challenges in Predictive Modeling • “First there are the known knowns” • These are the things that we know we know • “Then there are the known unknowns” • These are the things that we now know we do not know • “Finally there are also the unknown unknowns” • These are the things that we do not yet know we do not know • “And each day brings us a few more unknown unknowns” • Donald Rumsfeld, 2003

  6. Computational ADME/Tox models • Solubility • Absorption • Mutagenicity • Bioavailability • Metabolic stability • Blood-brain barrier permeability • Cardiac toxicity (hERG) • Plasma protein binding

  7. ADME/Tox vs Potency Space Christopher Lipinski & Andrew Hopkins, NATURE|VOL 432 | 16 DECEMBER 2004, pp.855-861

  8. Credibility issues that led to the “Rule of One” • “Computers in the future may weigh no more than 1.5 tons” – Popular Mechanics, 1949 • “I think there might be a market for maybe five computers” – Thomas Watson, IBM, 1943 • “There is no reason anyone would want a computer in their home” – Ken Olsen, founder of Digital Equipment Corporation, 1977 • “Who wants to hear actors talk?” – H.M. Warner, 1927 • “Forget it – no civil war picture ever made a nickel” – MGM executive, in 1937, advising against production of “Gone with the Wind”.

  9. Predictive ToxicologyChair: Curt Breneman (Rensselaer Polytechnic Institute) 08.45 Chair’s Introduction & Opening Remarks 09.00 Gilles Klopman (Multicase), Machine Intelligence in the Design of New Biologically Active Chemicals 09.30 Sanji Bhal & David Adams (ACD/Labs), An in silico Approach to Reduce the Burdens of Lead Discovery and Optimization 10.00 Bob Clark (Tripos), The "Structures" in Structure-Activity Relationships10.30 Navita Mallalieu (Roche Pharmaceuticals), A Roadmap for Integrating Modelling & Simulation in Pre-Clinical DMPK Research11.00 Coffee Break11.30 Curt Breneman (Rensselaer Polytechnic Institute), Predictive ADME : How do I know if my predictions will be useful? 12.00 Michael B. Bolger (Simulations Plus and USC School of Pharmacy), Integration of Early ADME using Property Estimation and PBPK Simulation12.30 Alex Tropsha (UNC), The statistical significance vs. mechanistic interpretation of ADME/tox models13.00 Lunch

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