The Glycine Receptor Allosteric Ligands Library (GRALL)

Abstract Motivation Glycine 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. Results Based 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 implementation The 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 [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

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iCn3D, a web-based 3D viewer for sharing 1D/2D/3D representations of biomolecular structures

Bioinformatics ◽

10.1093/bioinformatics/btz502 ◽

2019 ◽

Vol 36 (1) ◽

pp. 131-135 ◽

Cited By ~ 11

Author(s):

Jiyao Wang ◽

Philippe Youkharibache ◽

Dachuan Zhang ◽

Christopher J Lanczycki ◽

Renata C Geer ◽

...

Keyword(s):

Large Fraction ◽

3D Structure ◽

Supplementary Information ◽

Sequence Annotation ◽

Web Based ◽

The Public ◽

Molecular Features ◽

Density Maps ◽

3D Molecular Structure ◽

3D Representations

Abstract Motivation Build a web-based 3D molecular structure viewer focusing on interactive structural analysis. Results iCn3D (I-see-in-3D) can simultaneously show 3D structure, 2D molecular contacts and 1D protein and nucleotide sequences through an integrated sequence/annotation browser. Pre-defined and arbitrary molecular features can be selected in any of the 1D/2D/3D windows as sets of residues and these selections are synchronized dynamically in all displays. Biological annotations such as protein domains, single nucleotide variations, etc. can be shown as tracks in the 1D sequence/annotation browser. These customized displays can be shared with colleagues or publishers via a simple URL. iCn3D can display structure–structure alignments obtained from NCBI’s VAST+ service. It can also display the alignment of a sequence with a structure as identified by BLAST, and thus relate 3D structure to a large fraction of all known proteins. iCn3D can also display electron density maps or electron microscopy (EM) density maps, and export files for 3D printing. The following example URL exemplifies some of the 1D/2D/3D representations: https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html?mmdbid=1TUP&showanno=1&show2d=1&showsets=1. Availability and implementation iCn3D is freely available to the public. Its source code is available at https://github.com/ncbi/icn3d. Supplementary information Supplementary data are available at Bioinformatics online.

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Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the “blind docking” approach

Journal of Molecular Modeling ◽

10.1007/s00894-005-0057-z ◽

2005 ◽

Vol 12 (3) ◽

pp. 366-372 ◽

Cited By ~ 52

Author(s):

Bogdan Iorga ◽

Denyse Herlem ◽

Elvina Barré ◽

Catherine Guillou

Keyword(s):

Binding Site ◽

Nicotinic Receptors ◽

Allosteric Modulators ◽

Docking Approach ◽

Putative Binding Site

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A Cation- Interaction in the Binding Site of the Glycine Receptor Is Mediated by a Phenylalanine Residue

Journal of Neuroscience ◽

10.1523/jneurosci.2540-08.2008 ◽

2008 ◽

Vol 28 (43) ◽

pp. 10937-10942 ◽

Cited By ~ 53

Author(s):

S. A. Pless ◽

K. S. Millen ◽

A. P. Hanek ◽

J. W. Lynch ◽

H. A. Lester ◽

...

Keyword(s):

Binding Site ◽

Glycine Receptor ◽

Phenylalanine Residue

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Identification of Positive Allosteric Modulators of Glycine Receptors from a High-Throughput Screen Using a Fluorescent Membrane Potential Assay

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057116657779 ◽

2016 ◽

Vol 21 (10) ◽

pp. 1042-1053 ◽

Cited By ~ 11

Author(s):

Clara Stead ◽

Adam Brown ◽

Cathryn Adams ◽

Sarah J. Nickolls ◽

Gareth Young ◽

...

Keyword(s):

Membrane Potential ◽

High Throughput ◽

Glycine Receptor ◽

Functional Characterization ◽

In Vitro Assays ◽

Allosteric Modulators ◽

Inhibitory Neurotransmission ◽

Starting Point ◽

Positive Allosteric Modulators

Glycine receptor 3 (GlyRα3) is a ligand-gated ion channel of the cys-loop family that plays a key role in mediating inhibitory neurotransmission and regulation of pain signaling in the dorsal horn. Potentiation of GlyRα3 function is therefore of interest as a putative analgesic mechanism with which to target new therapeutics. However, to date, positive allosteric modulators (PAMs) of this receptor with sufficient selectivity to enable target validation studies have not been described. To address this lack of pharmacological tools, we developed a suite of in vitro assays comprising a high-throughput fluorescent membrane potential screen and a medium-throughput electrophysiology assay using IonFlux HT together with conventional manual patch clamp. Using these assays, we conducted a primary screening campaign and report the structures of hit compounds identified as GlyR PAMs. Our functional characterization data reveal a hit compound with high efficacy relative to current known potentiators and selectivity over GABAAR, another major class of inhibitory neurotransmission receptors of importance to pain. These small-molecule GlyR PAMs have high potential both as early tool compounds to enable pharmacological studies of GlyR inhibitory neurotransmission and as a starting point for the development of potent, selective GlyRα3 PAMs as novel analgesics.

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Molecular Modeling of a Tandem Two Pore Domain Potassium Channel Reveals a Putative Binding Site for General Anesthetics

ACS Chemical Neuroscience ◽

10.1021/cn500172e ◽

2014 ◽

Vol 5 (12) ◽

pp. 1246-1252 ◽

Cited By ~ 13

Author(s):

Edward J. Bertaccini ◽

Robert Dickinson ◽

James R. Trudell ◽

Nicholas P. Franks

Keyword(s):

Molecular Modeling ◽

Potassium Channel ◽

Binding Site ◽

General Anesthetics ◽

Pore Domain ◽

Putative Binding Site

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An Integrated Computational and Experimental Binding Study Identifies the DNA Binding Domain as the Putative Binding Site of Novel Pyrimidinetrione Signal Transducer and Activator of Transcription 3 (STAT3) Inhibitors

Drug Designing Open Access ◽

10.4172/2169-0138.1000142 ◽

2017 ◽

Vol 06 (01) ◽

Cited By ~ 1

Author(s):

Shan Sun ◽

Peibin Yue ◽

Mingzhu He ◽

Xiaolei Zhang ◽

David Paladino ◽

...

Keyword(s):

Dna Binding ◽

Binding Site ◽

Binding Domain ◽

Binding Study ◽

Dna Binding Domain ◽

Signal Transducer ◽

Transcription 3 ◽

Putative Binding Site

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Novel dynamic residue network analysis approaches to study homodimeric allosteric modulation in SARS-CoV-2 Mpro and in its evolutionary mutations

10.33774/chemrxiv-2021-7thm1 ◽

2021 ◽

Author(s):

Olivier Sheik Amamuddy ◽

Rita Afriyie Baoteng ◽

Victor Barozi ◽

Dorothy Wavinya Nyamai ◽

Ozlem Tastan Bishop

Keyword(s):

Binding Site ◽

Laboratory Strain ◽

Allosteric Modulators ◽

Allosteric Communication ◽

Katz Centrality ◽

Symmetry Problem ◽

The Stability ◽

Allosteric Mechanisms ◽

Domain I ◽

Communication Path

The rational search for allosteric modulators and the allosteric mechanisms of these modulators in the presence of evolutionary mutations, including resistant ones, is a relatively unexplored field. Here, we established novel in silico approaches and applied to SARS-CoV-2 main protease (Mpro). First, we identified six potential allosteric modulators (SANC00302, SANC00303, SANC00467, SANC00468, SANC00469, SANC00630) from the South African Natural Compounds Database (SANCDB) bound to the allosteric pocket of Mpro that we determined in our previous work. We also checked the stability of these compounds against Mpro of laboratory strain HCoV-OC43 and identified differences due to residue changes between the two proteins. Next, we focused on understanding the allosteric effects of these modulators on each protomer of the reference Mpro protein, while incorporating the symmetry problem in the functional homodimer. In general, asymmetric behavior of multimeric proteins is not commonly considered in computational analysis. We introduced a novel combinatorial approach and dynamic residue network (DRN) analysis algorithms to examine patterns of change and conservation of critical nodes, according to five independent criteria of network centrality (betweenness centrality (BC), closeness centrality (CC), degree centrality (DC), eigencentrality (EC) and katz centrality (KC)). The relationships and effectiveness of each metric in characterizing allosteric behavior were also investigated. We observed highly conserved network hubs for each averaged DRN metric on the basis of their existence in both protomers in the absence and presence of all ligands, and we called them persistent hubs (residues 17, 111, 112 and 128 for averaged BC; 6, 7, 113, 114, 115, 124, 125, 126, 127 and 128 for averaged CC; 36, 91, 146, 150 and 206 for averaged DC; 7, 115 and 125 for EC; 36, 125 and 146 for KC). We also detected ligand specific signal changes some of which were in or around functional residues (i.e. chameleon switch PHE140). Using EC persistent hubs and ligand introduced hubs we identified a residue communication path between allosteric binding site and catalytic site. Finally, we examined the effects of the mutations on the behavior of the protein in the presence of selected potential allosteric modulators and investigated the ligand stability. The hit compounds showed various levels of stability in the presence of SARS-CoV-2 Mpro mutations, being most stable in A173V, N274D and R279C, and least stable in R60C, N151D V157I, C160S and A255V. SANC00468 was the most stable compound in the 43 mutant protein systems. We further used DRN metric analysis to define cold spots as being those regions that are least impacted, or not impacted, by mutations. One crucial outcome of this study was to show that EC centrality hubs form an allosteric communication path between the allosteric ligand binding site to the active site going through the interface residues of Domain I and II; and this path was either weakened or lost in the presence of some of the mutations. Overall, the results of this study revealed crucial aspects that need to be considered in drug discovery in COVID-19 specifically and in general for rational computational drug design purposes.

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