Function-specific virtual screening for GPCR ligands using a combined scoring method

• DOI: 10.1038/srep28288
• Publication Date: 2016-06-24T09:14:42Z
• Authors: Albert J. Kooistra; Henry F. Vischer; Daniel McNaught-F...; Rob Leurs; Iwan J. P. de Esch; Chris de Graaf
• Keywords: Docking (animal); Inverse agonist

Abstract The ability of scoring functions to correctly select and rank docking poses small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe virtual screening method that combines an energy-based function with molecular interaction fingerprint (IFP) identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. consensus prospectively evaluated by: 1) the discovery chemically novel, fragment-like, high affinity histamine H 1 (H R) antagonists/inverse agonists, 2) selective identification ß 2 -adrenoceptor (ß agonists 3) experimental validation comparison combined individual approaches. Systematic retrospective simulations allowed definition cut-offs R selection optimal ß-adrenoceptor structure discrimination between antagonists. approach resulted 53% 73% hits up nanomolar affinities potencies. shows possibilities prediction GPCR ligand by integrating protein-ligand mode information.