Discovery of PRMT5 Inhibitors from Semiliquidambar Cathayensis Chang Using Computational and Bioactivity Evaluation.

BACKGROUND: PRMT5 (protein arginine methyltransferase 5) plays important physiological roles in the occurrence and development of various diseases, including cancer. Inhibiting the activity of PRMT5 is an effective strategy for alleviating these diseases. OBJECTIVE: To identify active compounds targeting PRMT5 from Semiliquidambar cathayensis Chang (S. cathayensis Chang). METHODS: Molecular docking and a PRMT5 enzyme assay were used to identify PRMT5 inhibitors from the chemical constituents of S. cathayensis Chang. Molecular dynamics simulations were further performed to elucidate the detailed interaction modes between these inhibitors and PRMT5. RESULTS: A comprehensive review of the extant literature was conducted to identify 101 chemical constituents of S. cathayensis Chang. Two PRMT5 inhibitors, (+)-catechin (13.33 ± 2.84 μM) and quercetin (0.85 ± 0.24 μM), were identified based on molecular docking and the PRMT5 enzyme assay. In the PRMT5-inhibitor complexes, PHE327, GLU435, and TRP579 were key amino acid residues, each contributing more than 1 kcal/mol to the binding free energy. DISCUSSION: The integrated computational approach and bioactivity evaluation provided an effective strategy for the rapid discovery of PRMT5 inhibitors from S. cathayensis Chang. This approach facilitated the identification of active compounds from structurally diverse natural products. CONCLUSION: Quercetin and (+)-catechin exhibited promising potential for further development owing to their PRMT5 inhibitory activity.