Drug–Target Interaction Deep Learning-Based Model Identifies the Flavonoid Troxerutin as a Candidate TRPV1 Antagonist

Based on the advances made by artificial intelligence (AI) technologies in drug discovery, including target identification, hit molecule identification, and lead optimization, this study investigated natural compounds that could act as transient receptor potential vanilloid 1 (TRPV1) channel protein antagonists. Using a molecular transformer drug–target interaction (MT-DTI) model, troxerutin was predicted to be a TRPV1 antagonist at IC50 582.73 nM. In a TRPV1-overexpressing HEK293T cell line, we found that troxerutin antagonized the calcium influx induced by the TRPV1 agonist capsaicin in vitro. A structural modeling and docking experiment of troxerutin and human TRPV1 confirmed that troxerutin could be a TRPV1 antagonist. A small-scale clinical trial consisting of 29 participants was performed to examine the efficacy of troxerutin in humans. Compared to a vehicle lotion, both 1% and 10% w/v troxerutin lotions reduced skin irritation, as measured by skin redness induced by capsaicin, suggesting that troxerutin could ameliorate skin sensitivity in clinical practice. We concluded that troxerutin is a potential TRPV1 antagonist based on the deep learning MT-DTI model prediction. The present study provides a useful reference for target-based drug discovery using AI technology and may provide useful information for the integrated research field of AI technology and biology.