Identification of novel selective TRPV3 antagonists based on virtual screening, molecular docking and bioassay / 药学学报

ABSTRACT

Transient receptor potential vanilloid member 3 (TRPV3) is a temperature-sensitive cation channel protein, which contributes to nociception, itch, hair growth, emotional control and the pathophysiology of migraine. However, research progress on TRPV3 fundamental molecular biology is rather slow, compared to other TRP channels due to the lack of its selective antagonists. It's necessary to identify TRPV3 selective antagonists for the study on TRPV3 physiological functions. In this study, several selective TRPV3 antagonists were identified by ligand-based virtual screening of shape-based similarity and electrostatic matching. The most potent one (V-39) blocked 2-APB-activated currents in a stable human TRPV3 expressed HEK293T cell line with IC50=18.0 ±1.1 μmol·L-1 (n=4). Besides, the interaction pattern between TRPV3 and its antagonists were studied through docking the antagonists into a homology model (TRPV3_HM4) generated from the crystal structure of TPRV1. The docking results show that the binding site of TRPV3 locates between linker domain (of N-terminus and TM1) and TRP Box. There are a π-π stacking interaction and hydrogen bonding interactions between compound V-39 and residues His-310, His-314 and Arg-577 of the pocket. Identification of these antagonists provides new probes for understanding the pharmacological function of TRPV3 channel.