Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold
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. Usin...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037023005020 |
| _version_ | 1827391213627506688 |
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| author | Èric Catalina-Hernández Mario López-Martín David Masnou-Sánchez Marco Martins Victor A. Lorenz-Fonfria Francesc Jiménez-Altayó Ute A. Hellmich Hitoshi Inada Antonio Alcaraz Yuji Furutani Alfons Nonell-Canals Jose Luis Vázquez-Ibar Carmen Domene Rachelle Gaudet Alex Perálvarez-Marín |
| author_facet | Èric Catalina-Hernández Mario López-Martín David Masnou-Sánchez Marco Martins Victor A. Lorenz-Fonfria Francesc Jiménez-Altayó Ute A. Hellmich Hitoshi Inada Antonio Alcaraz Yuji Furutani Alfons Nonell-Canals Jose Luis Vázquez-Ibar Carmen Domene Rachelle Gaudet Alex Perálvarez-Marín |
| author_sort | Èric Catalina-Hernández |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T17:07:28Z |
| format | Article |
| id | doaj.art-fec8ab2a92ba4a038f5fbb653e8b027b |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T17:07:28Z |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-fec8ab2a92ba4a038f5fbb653e8b027b2024-01-04T04:39:21ZengElsevierComputational and Structural Biotechnology Journal2001-03702024-12-0123473482Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffoldÈric Catalina-Hernández0Mario López-Martín1David Masnou-Sánchez2Marco Martins3Victor A. Lorenz-Fonfria4Francesc Jiménez-Altayó5Ute A. Hellmich6Hitoshi Inada7Antonio Alcaraz8Yuji Furutani9Alfons Nonell-Canals10Jose Luis Vázquez-Ibar11Carmen Domene12Rachelle Gaudet13Alex Perálvarez-Marín14Unit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, SpainUnit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, SpainUnit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, SpainUnit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, SpainInstituto de Ciencia Molecular, Universidad de Valencia, Catedrático José Beltrán-2, 46980 Paterna, SpainInstitute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Department of Pharmacology, Toxicology and Therapeutics,Institute of Neurosciences, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, SpainFriedrich Schiller University Jena, Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry & Macromolecular Chemistry, Humboldtstrasse 10, 07743 Jena, Germany; Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University, Max-von-Laue Str. 9, 60438 Frankfurt, GermanyDepartment of Biochemistry & Cellular Biology National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, JapanLaboratory of Molecular Biophysics, Dept. of Physics, Universitat Jaume I, 12071 Castellón, SpainDepartment of Life Science and Applied Chemistry, Nagoya Institute of Technology, Showa-Ku, Nagoya 466-8555, Japan; Optobiotechnology Research Center, Nagoya Institute of Technology, Showa-Ku, Nagoya 466-8555, JapanDevsHealth SL, 08530 La Garriga, Catalonia, SpainUniversité Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, FranceDept. of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UKDept of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USAUnit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain; Correspondence to: Unit of Biophysics, Dept. of Biochemistry and Molecular Biology, Facultat de Medicina, Av. Can Domènech s/n, Universitat Autònoma de Barcelona; 08193 Cerdanyola del Vallés, Catalonia, Spain.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.http://www.sciencedirect.com/science/article/pii/S2001037023005020Ion channelsTRP channelsTRPV2Drug discoveryMembrane proteinsBiophysics |
| spellingShingle | Èric Catalina-Hernández Mario López-Martín David Masnou-Sánchez Marco Martins Victor A. Lorenz-Fonfria Francesc Jiménez-Altayó Ute A. Hellmich Hitoshi Inada Antonio Alcaraz Yuji Furutani Alfons Nonell-Canals Jose Luis Vázquez-Ibar Carmen Domene Rachelle Gaudet Alex Perálvarez-Marín Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold Computational and Structural Biotechnology Journal Ion channels TRP channels TRPV2 Drug discovery Membrane proteins Biophysics |
| title | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold |
| title_full | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold |
| title_fullStr | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold |
| title_full_unstemmed | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold |
| title_short | Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold |
| title_sort | experimental and computational biophysics to identify vasodilator drugs targeted at trpv2 using agonists based on the probenecid scaffold |
| topic | Ion channels TRP channels TRPV2 Drug discovery Membrane proteins Biophysics |
| url | http://www.sciencedirect.com/science/article/pii/S2001037023005020 |
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