Homology Modeling and Docking Evaluation of Aminergic G Protein-Coupled Receptors

• DOI: 10.1021/ci900444q
• Publication Date: 2010-03-01T12:29:02Z
• Authors: Fiona M. McRobb; Ben Capuano; Ian T. Crosby; David K. Chalmers; Elizabeth Yuriev
• Keywords: Docking (animal); Homology; Molecular model; Loop modeling

We report the development of homology models dopamine (D2, D3, and D4), serotonin (5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C), histamine (H1), muscarinic (M1) receptors, based on high-resolution structure β2-adrenergic receptor. The were built refined using Prime. have addressed required modeling extracellular loop 2, which is often implicated in ligand binding. orthosteric sites optimized induced fit docking, to allow for side-chain flexibility, resulting receptor been evaluated protein validation tools. Of nine developed, six showed moderate good enrichment virtual screening experiments (5-HT2A, 5-HT1B, D2, 5-HT2C, M1). 5-HT2A displayed highest with factors 6.1, 6.9, 5.9 at 5, 10%, respectively, screened database. However, three require further refinement (5-HT2B, D4, H1), due difficulties some binding site residues as well 2. Our effort also aims supplement limited number tested G protein-coupled β2 crystal that are freely available research community.