In silico identification of food-grade cooling compounds targeting TRPM8 and TRPA1: A dual-target approach.

BACKGROUND: Oral mucosa is susceptible to pathological changes, including burning sensation, erythema, and inflammation, when exposed to thermal, mechanical, or chemical stimuli. These changes significantly impact oral comfort and health. To address the need for oral cooling agents, this study targets both TRPM8 and TRPA1 channels. We established a "computation-screening-validation" system using homology modeling and virtual screening to identify potential cooling agents from 555 natural flavorings approved for food use in China.

RESULTS: High-quality homology models of TRPM8 and TRPA1 were constructed. Multi-stage virtual screening was then performed using molecular docking. This process incorporated pharmacokinetic properties, key physicochemical properties (water solubility and lipophilicity), and Protox3.0 toxicity predictions. The structural stability of promising ligand-target complexes was further evaluated via molecular dynamics simulations. The screening identified α-Terpineol, cis-Jasmone, and Benzyl Salicylate as promising candidates. These compounds demonstrated superior predicted binding affinities for both targets compared to other screened compounds and favorable safety profiles. Molecular dynamics simulations confirmed stable binding and structural compactness of these compounds within the TRPM8 and TRPA1 binding sites.

CONCLUSIONS: This dual-target in silico approach offers an efficient, systematic way to identify safe and effective cooling agents. It provides valuable insights for the development of temperature-sensing modulators by highlighting compounds that can simultaneously activate TRPM8 and TRPA1.