Positive Modulators of Glycine Receptors with Analgesic Potential Identified by Virtual Screening

Abstract

Human glycine receptors (hGlyRs) are important targets for neuroactive drugs, including for analgesic therapies. A previous study has identified the crucial role of residue S296 in hGlyR-α1 potentiation by Δ9-tetrahydrocannabinol (THC) and in cannabinoid-induced analgesia. The recently determined NMR structure of the hGlyR-α1 transmembrane domain (TMD) provides a basis for structure-based virtual screening to discover new analgesic drugs. Using a large ensemble of hGlyR-α1 structures generated from molecular dynamics simulations based on the NMR structure, we screened 1549 FDA approved compounds from the DrugBank database targeted to a cannabinoid binding site near residue S296. Drugs were ranked based on their predicted binding affinities across the ensemble of hGlyR-α1 TMD structures. Four leading compounds were selected for experimental validation in Xenopus laevis oocytes expressing hGlyR-α1. At a low concentration (1 μM), all four leading compounds potentiate hGlyR-α1 currents more than two times, which was greater than that of THC. The hit rate is remarkable. The study provides strong evidence that these leading compounds will be at least as effective as THC for analgesia by acting on hGlyR-α1, but without psychoactive effects. The protocol developed here can easily be applied to the discovery of novel analgesic compounds of even higher efficacy on hGlyRs. Research supported by grants from the NIH and XSEDE.