Work

On the Applicability of GPCR Homology Models to Computer-Aided Drug Discovery: A Comparison between In Silico and Crystal Structures of the β2-Adrenergic Receptor

Year: 2008

Type: article

Abstract: The publication of the crystal structure of the beta2-adrenergic receptor (beta2-AR) proved that G protein-coupled receptors (GPCRs) share a structurally conserved rhodopsin-like 7TM core. Here, to probe to which extent realistic GPCR structures can be recreated through modeling, carazolol was docked at two rhodopsin-based homology models of the human beta 2-AR. The first featured a rhodopsin-like second extracellular loop, which interfered with ligand docking and with the orientation of several residues in the binding pocket. The second featured a second extracellular loop built completely de novo, which afforded a more accurate model of the binding pocket and a better docking of the ligand. Furthermore, incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket --Phe290(6.52)--, resulted in significantly improved docking poses. These results support the applicability of GPCR modeling to the design of site-directed mutagenesis experiments and to drug discovery.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/jm800044k

Author: Stefano Costanzi

Institutions: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases

Award: Molecular modeling of G protein-coupled receptors