Ensemble-based virtual screening for cannabinoid-like potentiators of the human glycine receptor α1 for the treatment of pain

Journal of Medicinal Chemistry
Marta M WellsPei Tang

Abstract

The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here, we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-α1 transmembrane domain (PDB ID: 2M6I ) and the critical role of residue S296 in hGlyR-α1 potentiation by Δ(9)-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR-α1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-α1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-α1. Only one compound showed no potentiation effects; seven potentiated hGlyR-α1 at a level greater than THC at 1 μM. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites.

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Citations

Oct 27, 2016·Physical Chemistry Chemical Physics : PCCP·Nan GaoXuemei Pu
Feb 2, 2017·Beilstein Journal of Organic Chemistry·Sumudu P Leelananda, Steffen Lindert
Jan 30, 2020·Physical Chemistry Chemical Physics : PCCP·Zhe WangTingjun Hou
Aug 10, 2017·Cellular and Molecular Life Sciences : CMLS·Hanns Ulrich ZeilhoferGonzalo E Yévenes
Jul 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lei YaoWei Xiong
Sep 30, 2018·Nature Communications·Qiang ChenPei Tang
Dec 12, 2019·Frontiers in Molecular Neuroscience·Rama Ashraf HusseinUlrike Breitinger
Jan 23, 2018·Analytical Chemistry·Nicholas A Ferraro, Michael Cascio
Sep 19, 2019·Journal of Chemical Information and Modeling·Roy González-AlemánLuis A Montero-Cabrera

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