Function-specific virtual screening for GPCR ligands using a combined scoring method
Docking (animal)
Inverse agonist
DOI:
10.1038/srep28288
Publication Date:
2016-06-24T09:14:42Z
AUTHORS (6)
ABSTRACT
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.
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