Structure-based Drug Discovery Using GPCR Homology Modeling: Successful Virtual Screening for Antagonists of the Alpha1A Adrenergic Receptor Export

@article{citeulike:3145328, abstract = {Abstract: In this paper, we describe homology modeling of the alpha1A receptor based on the X-ray structure of bovine rhodopsin. The protein model has been generated by applying ligand-supported homology modeling, using mutational and ligand SAR data to guide the protein modeling procedure. We performed a virtual screening of the company's compound collection to test how well this model is suited to identify alpha1A antagonists. We applied a hierarchical virtual screening procedure guided by 2D filters and three-dimensional pharmacophore models. The ca. 23 000 filtered compounds were docked into the alpha1A homology model with GOLD and scored with PMF. From the top-ranked compounds, 80 diverse compounds were tested in a radioligand displacement assay. 37 compounds revealed Ki values better than 10 M; the most active compound binds with 1.4 nM to the alpha1A receptor. Our findings suggest that rhodopsin-based homology models may be used as the structural basis for GPCR lead finding and compound optimization.}, address = {Aventis Pharma Deutschland GmBH, Ein Unternehmen der Sanofi-Aventis Gruppe, DI\&A Chemistry, Computational Chemistry, Industriepark H\"{o}chst, Building G838, D-65926 Frankfurt am Main, Germany}, author = {Evers, A. and Klabunde, T.}, citeulike-article-id = {3145328}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/jm0491804}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/jm0491804}, day = {24}, doi = {10.1021/jm0491804}, journal = {J. Med. Chem.}, keywords = {docking, gpcr, homology\_modeling, virtual\_screening}, month = {February}, number = {4}, pages = {1088--1097}, posted-at = {2008-08-21 16:34:16}, priority = {2}, title = {Structure-based Drug Discovery Using GPCR Homology Modeling: Successful Virtual Screening for Antagonists of the Alpha1A Adrenergic Receptor}, url = {http://dx.doi.org/10.1021/jm0491804}, volume = {48}, year = {2005} }

TY - JOUR ID - citeulike:3145328 L3 - citeulike-article-id:3145328 N2 - Abstract: In this paper, we describe homology modeling of the alpha1A receptor based on the X-ray structure of bovine rhodopsin. The protein model has been generated by applying ligand-supported homology modeling, using mutational and ligand SAR data to guide the protein modeling procedure. We performed a virtual screening of the company's compound collection to test how well this model is suited to identify alpha1A antagonists. We applied a hierarchical virtual screening procedure guided by 2D filters and three-dimensional pharmacophore models. The ca. 23 000 filtered compounds were docked into the alpha1A homology model with GOLD and scored with PMF. From the top-ranked compounds, 80 diverse compounds were tested in a radioligand displacement assay. 37 compounds revealed Ki values better than 10 M; the most active compound binds with 1.4 nM to the alpha1A receptor. Our findings suggest that rhodopsin-based homology models may be used as the structural basis for GPCR lead finding and compound optimization. IS - 4 JF - J. Med. Chem. AD - Aventis Pharma Deutschland GmBH, Ein Unternehmen der Sanofi-Aventis Gruppe, DI&A Chemistry, Computational Chemistry, Industriepark Höchst, Building G838, D-65926 Frankfurt am Main, Germany EP - 1097 TI - Structure-based Drug Discovery Using GPCR Homology Modeling: Successful Virtual Screening for Antagonists of the Alpha1A Adrenergic Receptor VL - 48 SP - 1088 KW - docking KW - gpcr KW - homology_modeling KW - virtual_screening AU - Evers, A AU - Klabunde, T PY - 2005/02/24/ UR - http://dx.doi.org/10.1021/jm0491804 ER -