Virtual screening identifies novel high-affinity σ 1 receptor ligands

The σ receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease, drug addiction, cancer, and pain. However, there are no high-throughput functional assays for σ receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ receptor. We screened a library of over 6 million compounds using the Schrödinger Glide package, followed by experimental characterization of top-scoring candidates. 77% of tested candidates bound σ1 with high affinity (10-550 nM). These include compounds with high selectivity for the σ receptor compared to the genetically unrelated but pharmacologically similar σ 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 σ receptor ligand discovery.