Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay

Meiling Shen; Lingfeng Li; Yue Li; Xi Gu; Longhui Bai; Chengfeng Xia; Wenyong Xiong; Zhili Zuo

doi:10.1016/j.bmc.2023.117477

Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay

Bioorg Med Chem. 2023 Oct 30:94:117477. doi: 10.1016/j.bmc.2023.117477. Epub 2023 Sep 15.

Authors

Meiling Shen¹, Lingfeng Li², Yue Li³, Xi Gu¹, Longhui Bai¹, Chengfeng Xia², Wenyong Xiong⁴, Zhili Zuo⁵

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education), School of Pharmacy, Yunnan University, Kunming 650091, China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
⁴ Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education), School of Pharmacy, Yunnan University, Kunming 650091, China. Electronic address: xwy@ynu.edu.cn.
⁵ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zuozhili@mail.kib.ac.cn.

PMID: 37738708
DOI: 10.1016/j.bmc.2023.117477

Abstract

The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca²⁺ into cells, thereby modulating cellular depolarization and intracellular ion concentration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (https://www.chemdiv.com) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca²⁺ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca²⁺ levels in hTRPC5-overexpressing HEK 293T cells, with IC₅₀ values of 10.2 μM and 10.3 μM, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.

Keywords: Ca(2+) channel; Inhibitors; TRPC5; Virtual screening.