Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold
Catalina-Hernández, Èric (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
López-Martín, Mario (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Masnou-Sánchez, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Martins, Marco (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Lorenz-Fonfria, Victor A. (Universidad de Valencia)
Jiménez Altayó, Francesc (Universitat Autònoma de Barcelona. Institut de Neurociències)
Hellmich, Ute A. (Goethe University, Germany)
Inada, Hitoshi (Department of Biochemistry & Cellular Biology National Center of Neurology and Psychiatry, Tokyo, Japan)
Alcaraz, Antonio (Universitat Jaume I)
Furutani, Yuji (Optobiotechnology Research Center, Nagoya Institute of Technology, Showa-Ku, Nagoya, Japan)
Nonell-Canals, Alfons (DevsHealth SL, La Garriga)
Vázquez-Ibar, Jose Luis (Université Paris-Saclay)
Domene, Carmen (University of Bath)
Gaudet, Rachelle (Harvard University)
Peralvarez-Marin, Alex (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)

Fecha:	2023
Resumen:	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 Ca 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.
Ayudas:	Agencia Estatal de Investigación PID2020-120222GB
Nota:	Catedres
Nota:	Altres ajuts: Ministerio de Universidades Margarita Salas Award (MGSD2021-10 to M.L.-M.); Universitat Autònoma De Barcelona Predoctoral Fellowship (B21P0033 to E.C.-H.); the Royal Society of Chemistry for Financial Support through a RS International Exchanges award (IES\R\193089 to C.D.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the collaborative research center 1507 "Membrane-associated Protein Assemblies, Machineries, and Supercomplexes" - Project ID 450648163 (to UAH); Cluster of Excellence "Balance of the Microverse" EXC2051 - Project-ID 390713860 (to UAH).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Ion channels ; TRP channels ; TRPV2 ; Drug discovery ; Membrane proteins ; Biophysics ; Docking ; Cardiovascular ; Computational biology ; Structural biology ; Pharmacology
Publicado en:	Computational and Structural Biotechnology Journal, Vol. 23 (december 2023) , p. 473-482, ISSN 2001-0370

DOI: 10.1016/j.csbj.2023.12.028
PMID: 38261868

10 p, 6.8 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Neurociències (INc)
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