High-quality ligand-steered modeling and docking evaluation of class A G protein-coupled receptors

CAVASOTTO, CLAUDIO N.; PHATAK, SHARANGDHAR S

Boston, MA

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

Using three GPCR structures as templates (beta2-adrenergic, A2A-adenosine, and rhodopsin receptors), we enhanced and validated the ligand-steered modeling method through cross-modeling of, and high-throughput docking on four target/template cases.  We raised and answered three questions: 1.      Can the ligand-steered modeling generate a small set of near-native models by using one structural template?  In all cases, the ligand-steered modeling method identified a small-set of models with at least one near-native model. 2.      How well do the ligand-steered models perform in docking?  The enrichment factor obtained by the best ligand-steered models was superior to those obtained by the crude models and random selection in all cases.  3.      How well do the ligand-steered models perform in assessing cross-selectivity between beta2 and A2A ligands? In all cases, the ligand-steered models either identified a higher percentage of target specific actives, and/or discarded higher percentage of ?other? actives, as compared to the crude models.