Virtual screening identifies novel high-affinity σ1 receptor ligands
Schmidt, H. R.; Greenfield, D. A.; Sliz, P.; Kruse, A. C.
Show abstract
The {sigma}1 receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease1, drug addiction2, cancer3, and pain4. However, there are no high-throughput functional assays for {sigma}1 receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the {sigma}1 receptor. We screened a library of over 6 million compounds using the Schrodinger Glide package, followed by experimental characterization of top-scoring candidates. 77% of tested candidates bound {sigma}1 with high affinity (10-550 nM). These include compounds with high selectivity for the {sigma}1 receptor compared to the genetically unrelated but pharmacologically similar {sigma}2 receptor, as well as compounds with substantial cross-reactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for {sigma}1 receptor ligand discovery.
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