Assessment and optimization of docking-based virtual screening for GPCR ligands: not only crystal structures but also homology models

COSTANZI, STEFANO; VILAR, SANTIAGO; FERINO, GIULIO; PHATAK, SHARANGDHAR S; BERK, BARKIN; CAVASOTTO, CLAUDIO N.

BOS

Conferencia; 240th National Meeting of the American-Chemical-Society; 2010

Using the Beta2-adrenergic receptor as a case study, we have investigated the applicability of crystal structures and homology models to the identification of GPCR ligands through docking-based virtual screening, and have defined methods intended to improve their performances. Our controlled computational performed at the receptor crystallized in complex with the inverse agonist carazolol yielded excellent results, with a clearly delineated prioritization of ligands over decoys. Blockers generally were preferred over agonists; however agonists were also well distinguished from decoys. Notably, this trend could be reversed by optimizing the receptor around a bound known agonist prior to the screen. Moreover, we devised a method to improve the general yields of the screen by generating an ensemble of alternative conformations of the receptor that accounts for its flexibility. Finally, we proved the applicability of docking-based virtual screenings also to homology models endowed with different of accuracy. This last point is of uttermost importance, since crystal structures are available only for a limited number of GPCRs, and extends our conclusions to the entire superfamily