A potential route of capsaicin to its binding site in the TRPV1 ion channel

Carmen Domene, Saul Gonzalez Resines, Victoria Oakes, Leonardo Darre Castell

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6 Citations (SciVal)


Transient receptor potential (TRP) ion channels are important pharmacological targets because of their role in the perception of pain, and so, understanding their chemical regulation is essential for the development of analgesic drugs. Among the currently known TRP channel chemical agonists, capsaicin, the active compound of chili pepper, is probably the most exhaustively studied. The availability of the three-dimensional structure of the vanilloid receptor 1 (TRPV1) has fueled computational studies revealing the molecular details of capsaicin binding modes. Although this is a significant step, a comprehensible binding mechanism or pathway is invaluable for targeting TRP channels in modern pharmacology. In the present work, free-energy and enhanced sampling techniques have been used to explore a possible membrane-mediated pathway for capsaicin to enter the TRPV1 binding pocket where capsaicin accesses the protein starting at the extracellular milieu through the outer leaflet and into its binding site in the protein. The main states visited along this route have been characterized and include (i) a bound state in agreement with the binding mode "head-down, tail-up"and (ii) an alternative state corresponding to a "head-up, tail-down"binding mode. In agreement with previous reports, binding is mediated by both hydrogen bonds and van der Waals interactions, and residue Y511 is crucial for stabilizing the bound state and during the binding process. Together, these results provide a foundation to further understand TRPV channels, and they could be used to guide therapeutic design of selective inhibitors potentially leading to novel avenues for pharmacological applications targeting the TRPV1 channel.

Original languageEnglish
Pages (from-to)2481-2489
JournalJournal of Chemical Information and Modeling
Issue number10
Early online date3 May 2022
Publication statusPublished - 23 May 2022

Bibliographical note

Funding Information:
C.D. acknowledges the use of the infrastructure at the U.K. National Supercomputing Service ARCHER ( http://www.archer.ac.uk ) and thanks PRACE for awarding access to computational resources in CSCS, the Swiss National Supercomputing Service, in the 17th and 20th Project Access Calls as well as preparatory access at ARCHER, the PDC Centre for High Performance Computing (PDC-HPC), CINECA, and the Jülich Supercomputing Center. Support from the Biotechnology and Biological Sciences Research Council and Pfizer Neusentis is also acknowledged (BB/L015269/1).

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences


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