Discovery of Promising USP21 Small Molecule Inhibitors: A Computational and Artificial Intelligence Modeling-Based Drug Repurposing Study for Non-Small Cell Lung Cancer

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.

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.

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.

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.