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

dc.contributor.authorDonate-Macian, P.
dc.contributor.authorDuarte, Y.
dc.contributor.authorRubio-Moscardo, F.
dc.contributor.authorPerez-Vilaro, G.
dc.contributor.authorCanan, J.
dc.contributor.authorDiez, J.
dc.contributor.authorGonzalez-Nilo, F.
dc.contributor.authorValverde, M.
dc.date.accessioned2021-08-06T03:12:22Z
dc.date.available2021-08-06T03:12:22Z
dc.date.issued2020
dc.descriptionIndexación: Scopus.es
dc.description.abstractBackground 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.es
dc.description.urihttps://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15267
dc.identifier.citationBritish Journal of Pharmacology, 2020es
dc.identifier.doiDOI: 10.1111/bph.15267
dc.identifier.issn0007-1188
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/19709
dc.language.isoenes
dc.publisherJohn Wiley and Sons Inces
dc.rights.licenseAttribution-NonCommercial 4.0 International (CC BY-NC 4.0)
dc.subjectantivirales
dc.subjectdrug discoveryes
dc.subjectHC067047es
dc.subjectin silicoes
dc.subjectinhibitiones
dc.subjectmolecular dynamicses
dc.subjectRN1734es
dc.subjectstructurees
dc.subjectTRPV4es
dc.subjectTransient Receptor Potential Channelses
dc.titleStructural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activityes
dc.typeArtículoes
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