Docking conformationally flexible molecules with MVP


Millard H. Lambert, Computational, Analytical and Structural Sciences, Computational, Analytical and Structural Sciences, Glaxo SmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398
MVP is a molecular mechanics program with facilities for docking, conformational search, library enumeration and homology modelling (Lambert, "Docking Conformationally Flexible Molecules into Protein Binding Sites," in Practical Application of Computer Aided Drug Design, Charifson, ed, (1997)). MVP was originally developed for protein structure prediction (Lambert and Scheraga, JCC 10 770-797, 798-816, 817-831, (1989)), and implements a generalized version of Harold Scheraga's build-up procedure. MVP can dock flexible organic molecules into a protein by running this build-up, or "grow" calculation within the binding site. This build-up process requires that the compound have an "anchor group" with approximately known position and orientation in the binding site. The anchor group is subjected to limited rotations and translations, but the procedure cannot usually predict large shifts in anchor position or orientation. These MVP docking calculations have been used in the structure based design of numerous compounds at Glaxo SmithKline, including eight clinical candidates, two of which are now in Phase II clinical trials. We will illustrate how the MVP build-up process works, and describe recent improvements, including methodology that makes it possible to dock compounds without any anchor group.

Docking and Scoring
9:00 AM-12:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004