Exploring bioactive phytoconstituents as USP21 inhibitors for therapeutic development against cancer.

Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease subfamily of deubiquitinating enzymes implicated in tumorigenesis and could be a target for anticancer therapy. Remarkably, it has been reported that overexpression and increased activity of USP21 are observed in various types of cancer, which explains the need for its novel small-molecule inhibitors. Plant-based compounds have emerged as promising candidates for therapeutic development due to their diverse biological activities and potential to modulate key molecular targets in disease pathways. In the present study, an integrated virtual screening strategy was adopted using IMPPAT 2.0. database to identify bioactive phytoconstituents that can potentially inhibit USP21. The selected compounds were subjected to physicochemical properties and binding affinity analysis for primary screening against USP21. Pharmacokinetic analysis, PASS evaluation, and interaction studies pinpointed two bioactive phytoconstituents, Ranmogenin A and Tokorogenin, as potential candidates against USP21. Further, molecular dynamics (MD) simulations for 500 ns were performed to analyze the conformational flexibility and stability of USP21-phytoconstituent complexes. The phytoconstituents were found to form stable protein-ligand complexes with USP21 throughout the simulation time. These findings provide a basis for subsequent research on Ranmogenin A and Tokorogenin as promising leads for drug development against USP21 in cancer treatment.