Abstract
The σ(1) 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(1) receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ(1) 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(1) with high affinity (K(D) < 1 μM). These include compounds with high selectivity for the σ(1) receptor compared to the genetically unrelated but pharmacologically similar σ(2) 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(1) receptor ligand discovery and provide compounds to prioritize in studies of σ(1) biology.