Virtual Screening for Ligand Discovery at the σ Receptor.

The σ receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease (J. Pharmacol. Sci.2015127 (1), 1729), drug addiction (Behav. Pharmacol.201627 (2-3 Spec Issue), 10015), cancer (Handb. Exp. Pharmacol.2017244237308), and pain (Neural Regener. Res.201813 (5), 775778). 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 σ with high affinity (K < 1 μM). 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 crossreactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ receptor ligand discovery and provide compounds to prioritize in studies of σ biology.