Discovery of Promising USP21 Small Molecule Inhibitors

Objectives: Ubiquitin specific protease 21 (USP21) is considered a novel lung cancer protein target. Research has revealed that USP21 is highly expressed in non–small cell lung cancer and its inhibition leads to decreased levels of the immune checkpoint inhibitor programmed death ligand 1 (PD-L1). Hence, targeting the USP21/ PD-L-1 interaction is a highly sought after therapeutic strategy. Methods: In this study, we applied an integrated methodology beginning with the refinement and optimization of the USP21 crystal structure via a novel computational and artificial intelligence- based modeling strategy. Our highly predicted chemical structure was used for screening of 6877 molecules, including investigational and FDA-approved drugs, along with a known potent USP21 inhibitor. We then performed 10 ns molecular dynamics (MD) simulations for select molecules, followed by 100 ns MD simulations for 29 lead molecules, along with post-MD MM/GBSA system free energy ΔG calculations. Results: Our comprehensive analysis led to the discovery of 7 molecules as the most promising USP21 inhibitors. These drugs are deslorelin, dotatate, vedroprevir, vasopressin, pentagastrin, furaprevir, and bleomycin, which is a currently approved anticancer drug used for the treatment of a variety of cancer types. Conclusions: Our results represent a strong scaffold that can be used by scientists, researchers, and chemists, opening the route for further drug design and discovery research. Drug repurposing offers a novel approach to identify potential cancer therapeutics and has the potential of making a significant impact on reducing the financial toxicity associated with oncology treatments for our patients.