Farhad Jahanfar
Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening
Jahanfar, Farhad; Sadofsky, Laura; Morice, Alyn; D’Amico, Massimo
Authors
Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Senior Lecturer in Respiratory Medicine
Professor Alyn Morice A.H.Morice@hull.ac.uk
Foundation Chair and Professor of Respiratory Medicine
Massimo D’Amico
Abstract
Transient Receptor Potential Melastatin 8 (TRPM8) from the melastatin TRP channel subfamily is a non-selective Ca2+-permeable ion channel with multimodal gating which can be activated by low temperatures and cooling compounds, such as menthol and icilin. Different conditions such as neuropathic pain, cancer, overactive bladder syndrome, migraine, and chronic cough have been linked to the TRPM8 mode of action. Despite the several potent natural and synthetic inhibitors of TRPM8 that have been identified, none of them have been approved for clinical use. The aim of this study was to discover novel blocking TRPM8 agents using automated patch clamp electrophysiology combined with a ligand-based virtual screening based on the SwissSimilarity platform. Among the compounds we have tested, nebivolol and carvedilol exhibited the greatest inhibitory effect, with an IC50 of 0.97 ± 0.15 µM and 9.1 ± 0.6 µM, respectively. This study therefore provides possible candidates for future drug repurposing and suggests promising lead compounds for further optimization as inhibitors of the TRPM8 ion channel.
Citation
Jahanfar, F., Sadofsky, L., Morice, A., & D’Amico, M. (2022). Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening. Membranes, 12(10), Article 954. https://doi.org/10.3390/membranes12100954
Journal Article Type | Article |
---|---|
Acceptance Date | Sep 24, 2022 |
Online Publication Date | Sep 28, 2022 |
Publication Date | Oct 1, 2022 |
Deposit Date | Oct 19, 2022 |
Publicly Available Date | Oct 20, 2022 |
Journal | Membranes |
Electronic ISSN | 2077-0375 |
Publisher | MDPI |
Peer Reviewed | Peer Reviewed |
Volume | 12 |
Issue | 10 |
Article Number | 954 |
DOI | https://doi.org/10.3390/membranes12100954 |
Keywords | TRPM8; Repurposing; Nebivolol; Carvedilol; Automated patch clamp |
Public URL | https://hull-repository.worktribe.com/output/4100188 |
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Copyright Statement
Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://cre‐ ativecommons.org/licenses/by/4.0/)
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