The Glycine Receptor Allosteric Ligands Library (GRALL).

Adrien H Cerdan,Marion Sisquellas,Marco Cecchini,Gilberto Pereira,Diego E Barreto Gomes,Jean-Pierre Changeux,Arne Elofsson

doi:10.1093/bioinformatics/btaa170

Abstract

MotivationGlycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels.ResultsBased on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL. This collection includes agonists, antagonists, positive and negative allosteric modulators and a number of experimentally inactive compounds. Most importantly, for a large fraction of them a structural annotation based on their putative binding site on the receptor is provided. This type of annotation, which is currently missing in other drug banks, along with the availability of cooperativity factors from radioligand displacement experiments are expected to improve the predictivity of in silico methodologies for allosteric drug discovery and boost the development of conformation-based pharmacological approaches.Availability and implementationThe GRALL library is distributed as a web-accessible database at the following link: https://ifm.chimie.unistra.fr/grall. For each molecular entry, it provides information on the chemical structure, the ligand-binding site, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges as determined by our in-house pipeline.Contact mcecchini@unistra.fr Supplementary information Supplementary data are available at Bioinformatics online.

Highlights

Glycine receptors (GlyR) are pentameric ligand-gated ion channels that mediate fast inhibitory neurotransmission in the spinal cord, brainstem, and the retina (Lynch, 2004)
X-ray crystallography of GABAA receptor chimeras demonstrated the existence of two neurosteroidbinding sites in the transmembrane domain of anionic pentameric ligand-gated ion channels (pLGICs), one for potentiation and one for inhibition (Laverty et al, 2017), whose relevance has been corroborated by subsequent X-ray crystallography of other GABAAR constructs solved in complex with pregnanolone (Miller et al, 2017) and alphaxalone (Chen et al, 2018)
We have reported on the GRALL database, which is a carefully curated, web-accessible library of small-molecule modulators of glycine receptors (GlyR)

Summary

Introduction

Glycine receptors (GlyR) are pentameric ligand-gated ion channels (pLGICs) that mediate fast inhibitory neurotransmission in the spinal cord, brainstem, and the retina (Lynch, 2004). We provide here a curated database of small molecule modulators with documented activity at homomeric GlyR-α1 and GlyR-α3 This library named GRALL, i.e. the Glycine Receptor Allosteric Ligands Library, includes 218 unique chemical structures shipped with 3D molecular geometries and quantummechanical charges, which are ready for use in in-silico pharmacology studies. Based on the existing literature (Lynch et al, 2017), (Zeilhofer et al, 2018) and references therein and more recent publications, a collection of 218 unique small molecules with documented modulatory activity on GlyR-α1 and α3 has been compiled This collection named GRALL contains several agonists and antagonists, a large number of positive and negative allosteric modulators and a significant fraction of experimentally inactive compounds.

Conclusions

Findings

Material and Methods