Investigating the potential of natural compounds and known drugs against obstructive airway inflammation in inhibiting TRPC6

Abstract

Investigating the potential of natural compounds and known drugs against obstructive airway inflammation in inhibiting TRPC6 Uzma Saqib a,1, Isaac S. Demaree b,1, Alexander G. Obukhov b,c, Krishnan Hajela a,* a School of Life Sciences, Devi Ahilya Vishwavidyalaya, Vigyan Bhawan, Khandwa Road Campus, Indore, 452 001, MP, India b Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA c Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA A R T I C L E I N F O Handling Editor: Prof A Angelo Azzi A B S T R A C T The Transient Receptor Potential Canonical 6 (TRPC6) channel was implicated in the pathogenesis of pulmonary airway inflammation, chronic obstructive pulmonary disease, pulmonary edema, and pulmonary fibrosis. It was also proposed that Ca2+ influx through TRPC6 may contribute to triggering pulmonary inflammatory responses. The ChEMBL database lists 44 drugs that are clinically used to treat asthma, a type of obstructive airway inflammation (OAI). Since the mode of action and targets are not fully elucidated for many of these 44 drugs, we used computational approaches to determine the drugs’ potential to interact with the inhibitor binding site on the TRPC6 protein. We also screened a library of natural compounds to retrieve the phytochemicals with a potential to interact with TRPC6. The binding affinities of two well-known TRPC6 inhibitors, BTDM and 2-aminoethoxydiphenyl borate (2-APB), were compared with those of the screened compounds. We found that despite stable in silico binding and a well-defined three-dimensional molecular interaction pattern with the TRPC6 protein of the two top-scoring compounds, montelukast and solanesol, the molecules from the approved-drug and natural-compound libraries respectively, failed to show any significant efficacy in the in vitro assays.