PT  - JOURNAL ARTICLE
AU  - Daniel A. Greenfield
AU  - Hayden R. Schmidt
AU  - Piotr Sliz
AU  - Andrew C. Kruse
TI  - Virtual screening identifies novel high-affinity σ<sub>1</sub> receptor ligands
AID  - 10.1101/699793
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 699793
4099  - http://biorxiv.org/content/early/2019/07/16/699793.short
4100  - http://biorxiv.org/content/early/2019/07/16/699793.full
AB  - The σ1 receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease1, drug addiction2, cancer3, and pain4. 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 (10-550 nM). 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 cross-reactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ1 receptor ligand discovery.NMDAN-methyl-D-aspartateECFPExtended Connectivity FingerprintsHTVSHigh Throughput Virtual ScreeningSPStandard Precision Virtual ScreeningXPExtra Precision Virtual Screening4-IBPN-(benzylpiperidin-4yl)-4-iodobenzamidePD1444181,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridineNE-100N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ehthylamine monohydrochlorideDTG1,3-Di-(2-tolyl)guanidine