Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities

Abstract

Introduction: A myriad of cellular pathophysiological responses are mediated by polymodal ion channels that respond to chemical and physical stimuli such as thermoTRP channels. Intriguingly, these channels are pivotal therapeutic targets with limited clinical pharmacology. In silico methods offer an unprecedented opportunity for discovering new lead compounds targeting thermoTRP channels with improved pharmacological activity and therapeutic index. Areas covered: This article reviews the progress on thermoTRP channel pharmacology because of (i) advances in solving their atomic structure using cryo-electron microscopy and, (ii) progress on computational techniques including homology modeling, molecular docking, virtual screening, molecular dynamics, ADME/Tox and artificial intelligence. Together, they have increased the number of lead compounds with clinical potential to treat a variety of pathologies. We used original and review articles from Pubmed (1997–2020), as well as the clinicaltrials.gov database, containing the terms thermoTRP, artificial intelligence, docking, and molecular dynamics. Expert opinion: The atomic structure of thermoTRP channels along with computational methods constitute a realistic first line strategy for designing drug candidates with improved pharmacology and clinical translation. In silico approaches can also help predict potential side-effects that can limit clinical development of drug candidates. Together, they should provide drug candidates with upgraded therapeutic properties.