Incorporating Protein Flexibility in Virtual Screening

GATICA, EDGAR A.; CAVASOTTO, CLAUDIO N.

Houston, TX

Jornada; Graduate School and Internship Fair; 2008

Typical structure-based virtual screeninguses a flexible ligand-rigid receptor docking approach.  This method fails to account for theinduced-fit effects, in which the receptor flexes upon ligand binding.  As a result, the docking algorithm may failto dock a known binder to a rigid receptor. Incorporating receptor flexibility may be necessary to ensure properdocking in cases where rigid receptor docking is unsuccessful.  However, explicitflexible-ligand:flexible-receptor docking is computationally too expensive foruse in large-scale virtual screening experiments.  An alternative strategy, which has shownimpressive results, is the use of multiple rigid receptors to simulate a singleflexible one.  The docking scores arethen merged, and the resulting list is condensed to a size equivalent to thatof a single screening (the merging-shrinking procedure).  Unfortunately, previous attempts to use thismethod have shown mixed results.  Wehypothesize that this is due to the inclusion of redundant receptorcombinations, that is, combinations of too similar receptors, what does notimprove ?but dilutes- the performance of the method.