Virtual Screening for Ligand Discovery at the σ1 Receptor

The σ1 receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease ( J. Pharmacol. Sci. 2015 127 1 17 29 ), drug addiction ( Behav. Pharmacol. 2016 27 2–3 Spec Issue 100 15 ), cancer ( Handb. Exp. Pharmacol. 2017 244 237 308 ), and pain ( Neural Regener. Res. 2018 13 5 775 778 ). However, there are no high-throughput functional assays for σ1 receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ1 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 (KD < 1 μM). These include compounds with high selectivity for the σ1 receptor compared to the genetically unrelated but pharmacologically similar σ2 receptor, as well as compounds with substantial crossreactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ1 receptor ligand discovery and provide compounds to prioritize in studies of σ1 biology.