Structure- and Ligand-Based Virtual Screening for Identification of Novel TRPV4 Antagonists

Area of Science:

• Pharmacology and Drug Discovery
• Molecular Biology
• Computational Chemistry

Background:

• Transient Receptor Potential Vanilloid 4 (TRPV4) channels are implicated in pain and inflammatory signaling pathways.
• TRPV4 represents a promising therapeutic target, yet clinical development of TRPV4 inhibitors is limited.
• A high-resolution structure of human TRPV4 (hTRPV4) was unavailable, necessitating the use of comparative modeling.

Purpose of the Study:

• To identify novel small molecules that inhibit human TRPV4 (hTRPV4) channel activity.
• To explore structure- and ligand-based virtual screening methods for discovering potential drug candidates.
• To evaluate the inhibitory potential of natural stilbenoids against hTRPV4.

Main Methods:

• Employed structure-based virtual screening using a comparative model of hTRPV4 and molecular docking.
• Utilized ligand-based virtual screening based on pharmacophoric features of known TRPV4 antagonists.
• Validated identified hits using a FLIPR^tetra assay to measure hTRPV4 inhibition; determined IC₅₀ values.

Main Results:

• Screening identified five potential hTRPV4 inhibitory compounds.
• All tested compounds demonstrated inhibition of hTRPV4 at 30 µM.
• Compound Z1213735368 exhibited potent inhibition with an IC₅₀ of 8 µM.
• Natural stilbenoids were assessed for their hTRPV4 binding and inhibitory capacity.

Conclusions:

• The study successfully identified novel hTRPV4 inhibitors through integrated virtual screening approaches.
• Compound Z1213735368 is a promising lead for developing therapeutics targeting TRPV4.
• Findings offer insights into hTRPV4 structural determinants, facilitating future drug development efforts.