Structure-based drug discovery using GPCR homology modeling: successful virtual screening for antagonists of the alpha1A adrenergic receptor.
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 K(i) values better than 10 microM; 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.
Evers
Andreas
A
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. Andreas.Evers@sanofi-aventis.com
Klabunde
Thomas
T
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009285:Naphthoquinones / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D011724:Pyridazines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D009285:Naphthoquinones; D010879:Piperazines; D011724:Pyridazines; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; D012243:Rhodopsin