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Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold
dc.contributor.author | Catalina-Hernández, Èric | |
dc.contributor.author | López-Martín, Mario | |
dc.contributor.author | Masnou-Sánchez, David | |
dc.contributor.author | Martins, Marco | |
dc.contributor.author | Lorenz Fonfria, Victor A. | |
dc.contributor.author | Jiménez-Altayó, Francesc | |
dc.contributor.author | Hellmich, Ute A. | |
dc.contributor.author | Inada, Hitoshi | |
dc.contributor.author | Alcaraz, Antonio | |
dc.contributor.author | Furutani, Yuji | |
dc.contributor.author | Nonell-Canals, Alfons | |
dc.contributor.author | Vázquez-ibar, José Luis | |
dc.contributor.author | Domene, Carmen | |
dc.contributor.author | Gaudet, Rachelle | |
dc.contributor.author | Perálvarez-Marín, Alex | |
dc.date.accessioned | 2024-05-15T12:12:41Z | |
dc.date.available | 2024-05-15T12:12:41Z | |
dc.date.issued | 2023-12-29 | |
dc.identifier.citation | CATALINA-HERNÁNDEZ, Èric, et al. Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold. Computational and Structural Biotechnology Journal, 2024, vol. 23, p. 473-482. | ca_CA |
dc.identifier.uri | http://hdl.handle.net/10234/207350 | |
dc.description.abstract | TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target. | ca_CA |
dc.format.extent | 10 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Elsevier | ca_CA |
dc.relation | Membrane-associated Protein Assemblies, Machineries, and Supercomplexes | ca_CA |
dc.rights | © 2024 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. | ca_CA |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | ca_CA |
dc.subject | ion channels | ca_CA |
dc.subject | TRP channels | ca_CA |
dc.subject | TRPV2 | ca_CA |
dc.subject | drug discovery | ca_CA |
dc.subject | membrane proteins | ca_CA |
dc.subject | biophysics | ca_CA |
dc.subject | docking | ca_CA |
dc.subject | cardiovascular | ca_CA |
dc.subject | computational biology | ca_CA |
dc.subject | structural biology | ca_CA |
dc.subject | pharmacology | ca_CA |
dc.title | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1016/j.csbj.2023.12.028 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
project.funder.identifier | ID 390713860 | ca_CA |
project.funder.name | MCIN/AEI/10.13039/501100011033 | ca_CA |
project.funder.name | Ministerio de Ciencia, Innovación y Universidades. Margarita Salas Award | ca_CA |
project.funder.name | Universitat Autònoma De Barcelona | ca_CA |
project.funder.name | Royal Society of Chemistry | ca_CA |
project.funder.name | Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) | ca_CA |
project.funder.name | Cluster of Excellence “Balance of the Microverse” EXC 2051 | ca_CA |
oaire.awardNumber | PID2020–120222GB-I00 | ca_CA |
oaire.awardNumber | MGSD2021-10 | ca_CA |
oaire.awardNumber | B21P0033 | ca_CA |
oaire.awardNumber | IES\R3\193089 | ca_CA |
oaire.awardNumber | ID 450648163 | ca_CA |
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