Virtual Screening for Ligand Discovery at the σ1 Receptor

The sigma(1) receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease (J. Pharmacol. Sci.201512711729), drug addiction (Behav. Pharmacol.2016272-3 Spec Issue10015), cancer (Handb. Exp. Pharmacol.2017244237308), and pain (Neural Regener. Res.2018135775778). 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 (K-D < 1 mu M). 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 crossreactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for sigma(1) receptor ligand discovery and provide compounds to prioritize in studies of sigma(1) biology.