TY - JOUR
T1 - Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold
AU - Catalina-Hernández, Èric
AU - López-Martín, Mario
AU - Masnou-Sánchez, David
AU - Martins, Marco
AU - Lorenz-Fonfria, Victor A
AU - Jiménez-Altayó, Francesc
AU - Hellmich, Ute A
AU - Inada, Hitoshi
AU - Alcaraz, Antonio
AU - Furutani, Yuji
AU - Nonell-Canals, Alfons
AU - Vázquez-Ibar, Jose Luis
AU - Domene, Carmen
AU - Gaudet, Rachelle
AU - Perálvarez-Marín, Alex
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2023/12/29
Y1 - 2023/12/29
N2 - 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.
AB - 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.
KW - Biophysics
KW - Cardiovascular
KW - Computational biology
KW - Docking
KW - Drug discovery
KW - Ion channels
KW - Membrane proteins
KW - Pharmacology
KW - Structural biology
KW - TRP channels
KW - TRPV2
UR - http://www.scopus.com/inward/record.url?scp=85181670632&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/b3872799-ad10-3616-b195-2e4e9fd71f6c/
U2 - 10.1016/j.csbj.2023.12.028
DO - 10.1016/j.csbj.2023.12.028
M3 - Article
C2 - 38261868
SN - 2001-0370
VL - 23
SP - 473
EP - 482
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -