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Updated: Aug 19, 2026

Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
Published on: June 28, 2019
Structure-based drug discovery using GPCR homology modeling: successful virtual screening for antagonists of the
Andreas Evers1, Thomas Klabunde
1Aventis 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
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 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.
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