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| John Irwin is a research scientist in the Department of Pharmaceutical Chemistry at the University of California, San Francisco in the group of Brian Shoichet. Dr. Irwin received his PhD in Organic Chemistry at the ETH in Zurich in 1991. After working briefly at a startup company developing molecular modeling software, he joined the lab of Gerard Bricogne at the MRC Laboratory of Molecular Biology in Cambridge, England developing new methods of macromolecular structure determination. He developed one of the early web-based graphical interfaces in structural biology. He went on to join the Macromolecular Structural Database project at the EMBL-EBI also in Cambridge where he was part of a team transforming the Protein Databank into an Oracle database and developing research tools. He joined the Shoichet Lab while still at Northwestern in 2000 and moved to UCSF in 2003. His work focuses on improving virtual screening methods, and on lowering the barriers to entry to docking for non-specialists. Dr. Irwin has consulted on drug discovery projects for a number of pharmaceutical companies.
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You can't find what's not there: the importance and the pitfalls of multiple representations of molecules in dockable databases
John Irwin, Pharmaceutical Chemistry, UCSF, 1700 4th St, Suite 501D, San Francisco CA 94143-2550 USA
The ZINC database of purchasable compounds for virtual screening is built largely from supplier catalogs available in 2D SDF format. To prepare a database for docking, we generate a 3D structure, and consider protonation, charge, and tautomeric form. If there is stereo-or regio-chemical ambiguity in the source file, that must also be addressed. One approach to uncertainty is to make an educated guess at a single representation. The approach we have taken in ZINC is to prepare multiple forms of the molecule that may be relevant. The downside to such sampling is one may create new decoys - docking hit lists may be overwhelmed by high scoring but physiologically irrelevant molecular representations, presenting new challenges to scoring functions. This talk will enumerate some of the choices to be made, describe our own strategy in some detail, and discuss examples that illustrate the advantages and disadvantages of using multiple representations of molecules in dockable databases.
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