Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity

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• dc.contributor.author Doñate-Macián, Pau
• dc.contributor.author Duarte, Yorley
• dc.contributor.author Rubio Moscardo, Fanny
• dc.contributor.author Pérez Vilaró, Gemma, 1985-
• dc.contributor.author Canan, Jonathan
• dc.contributor.author Díez Antón, Juana, 1962-
• dc.contributor.author González Nilo, Fernando
• dc.contributor.author Valverde, M. A. (Miguel Ángel), 1963-
• dc.date.accessioned 2020-11-04T07:07:48Z
• dc.date.available 2020-11-04T07:07:48Z
• dc.date.issued 2022
• dc.description.abstract Background and purpose: The transient receptor potential vanilloid 4 (TRPV4) cation channel participates in multiple physiological processes and is also at the core of different diseases, making this channel an interesting pharmacological target with therapeutic potential. However, little is known about the structural elements governing its inhibition. Experimental approach: We have now combined in silico drug discovery and molecular dynamics simulation based on Xenopus tropicalis xTRPV4 structure with functional studies measuring cell Ca2+ influx mediated by human TRPV4 channel to characterize the binding site of known TRPV4 inhibitors and to identify novel small molecule channel modulators. Key results: We have found that the inhibitor HC067047 binds to a pocket conformed by residues from S2-S3 linker (xTRPV4-D542), S4 (xTRPV4-M583 and Y587 and S5 (xTRPV4-D609 and F613). This pocket was also used for structure-based virtual screening in the search of novel channel modulators. Forty potential hits were selected based on the lower docking scores (from ~250,000 compounds) and their effect upon TRPV4 functionally tested. Three were further analysed for stability using molecular dynamics simulation and functionally tested on TRPV4 channels carrying mutations in the binding pocket. Compound NSC151066, shown to require residue xTRPV4-M583 for its inhibitory effect, presented an IC50 of 145 nM and demonstrated to be an effective antiviral against Zika virus with a potency similar to HC067047. Conclusion and implications: Together, we propose structural insights into the inhibition of TRPV4 and how this information can be used for the design of novel channel modulators.
• dc.description.sponsorship We thank Dr. Andres Merits (University of Tartu, Estonia) for kindly providing the plasmid encoding the ZIKV with NanoLuc, Spanish Ministry of Economy and Competitiveness through grants RTI2018‐099718 (to M.A.V.) and BFU2016‐80039‐R (to J.D.), an institutional “Unidad de Excelencia María de Maeztu” CEX2018‐000792‐M and FEDER funds. F.G.‐N. thanks Fondecyt Regular projects 1170733, the US Army of USA, W911NF‐14‐1‐0520 and The Centro Interdisciplinario de Neurociencia de Valparaíso is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo P029‐022‐F.
• dc.format.mimetype application/pdf
• dc.identifier.citation Doñate-Macian P, Duarte Y, Rubio-Moscardo F, Pérez-Vilaró G, Canan J, Díez J, González-Nilo F, Valverde MA. Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity. Br J Pharmacol. 2022 Jul;179(14):3576-91. DOI: 10.1111/bph.15267
• dc.identifier.doi http://dx.doi.org/10.1111/bph.15267
• dc.identifier.issn 0007-1188
• dc.identifier.uri http://hdl.handle.net/10230/45652
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Br J Pharmacol. 2022 Jul;179(14):3576-91
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016‐80039‐R
• dc.rights © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword HC067047
• dc.subject.keyword RN1734
• dc.subject.keyword TRPV4
• dc.subject.keyword Antiviral
• dc.subject.keyword Drug discovery
• dc.subject.keyword In silico
• dc.subject.keyword Inhibition
• dc.subject.keyword Molecular dynamics
• dc.subject.keyword Structure
• dc.title Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion