Computational discovery, structural optimization and biological evaluation of novel inhibitors targeting transient receptor potential vanilloid type 3 (TRPV3)

Bioorg Chem. 2021 Sep:114:105093. doi: 10.1016/j.bioorg.2021.105093. Epub 2021 Jun 13.

Abstract

Transient receptor potential vanilloid type 3 (TRPV3) is a Ca2+ permeable nonselective cation channel and expressed abundantly in skin keratinocytes. TRPV3 emerges as an attractive target for treatment of pruritic, inflammatory, pain and skin-related diseases. However, only a few reports of TRPV3 inhibitors exist at present besides some patents. Therefore, TRPV3 research has always been fraught with challenges. Through a combination of virtual screening and biological evaluation, compound P1 (10 μM) was identified as a top hit with 34.5% inhibitory effect on 2-APB (1 mM)-evoked currents of mTRPV3-WT. Further structural optimization provided the inhibitor PC5 with the best activity (IC50 = 2.63 ± 0.28 μM), and point mutation assays indicated that amino acids V629 and F633 are crucial for the binding of PC5 and TRPV3. In summary, these newly discovered inhibitors could serve as promising lead compounds for the development of TRPV3 inhibitors in the future.

Keywords: Point mutation; Small-molecule inhibitor; TRPV3; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation*
  • Molecular Structure
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*

Substances

  • Benzamides
  • Small Molecule Libraries
  • TRPV Cation Channels
  • TRPV3 protein, human