Identification of potential inhibitors of Ubiquitin carboxyl-terminal hydrolase 21 from repurposed drugs: Implications in anticancer therapeutics

Ubiquitin carboxyl-terminal hydrolase 21 (USP21) is involved in the regulation of multiple cellular processes and participates in tumorigenesis. Due to its importance in the onset and progression of cancer, USP21 has become an appealing target in anticancer drug discovery. Therefore, this study aimed to screen a collection of repurposed drugs from the DrugBank 6.0 database for possible USP21 inhibitors. At the beginning of the selection process, the library was filtered by the binding efficiency to USP21, which identified a few drug molecules with appreciable binding affinity towards the USP21 binding pocket. These shortlisted molecules were then scrutinized based on their drug profiles and biological activities, with reference to their anticancer potential. Among them, Nilotinib and Radotinib were identified as the top candidates, with higher Pa values for anticancer activity. The interaction analysis and molecular dynamics (MD) simulation study further confirmed that both Nilotinib and Radotinib bind to the important and common residues of the USP21 binding site, which may inhibit the aberrant activity of USP21 in pathological conditions. The 500 ns MD simulations showed that both drugs are capable of binding to USP21 without any significant structural changes, which justifies their likelihood of being used as repurposed agents for cancer treatment. The RMSD, Rg, and hydrogen bond analyses showed minimal fluctuations, indicating high conformational stability. Additionally, free energy landscape (FEL) analysis supported the stability of the complexes. These results suggest that Nilotinib and Radotinib could serve as promising repurposed agents for USP21 inhibition in cancer treatment after required validation. In conclusion, the combination of docking and MD simulations highlights their potential therapeutic relevance, laying the groundwork for further development of USP21 inhibitors as anticancer drugs.