Targeting Ubiquitin-Specific Protease 7 (USP7): A Pharmacophore-Guided Drug Repurposing and Physics-Based Molecular Simulation Study

Ubiquitin-specific protease 7 (USP7) is a key regulator of tumor suppressors, oncoproteins, and epigenetic machinery, making it a compelling target for cancer therapy. Overexpression of USP7 correlates with worse survival of patients with multiple types of cancer, including multiple myeloma, and has been shown to contribute to chemoresistance. Here, we represent a structure-based drug repurposing pipeline to identify novel USP7 inhibitors from a curated library of 6654 FDA-approved and investigational small molecules. Using structure-based pharmacophore models derived from USP7-ligand crystal structures, we screened and prioritized hits based on pharmacophoric compatibility. The top 100 hits were subjected to short 10-ns molecular dynamics (MD) simulations and MM/GBSA binding free energy calculations, narrowing down to 36 promising ligands. These were further evaluated through longer (100 ns) MD simulations, binding energy refinement, ligand clustering based on molecular fingerprints, and cancer-specific activity predictions using a binary QSAR model. By integrating our findings, we propose 12 drugs as the most promising lead molecules: carafiban, alnespirone, morclofone, etofylline clofibrate, xantifibrate, cefmatilenum, cefovecin, puromycin, troglitazone, droxicam, vidarabine, and furbucillin. Further in vitro biological activity testing and validation of these potential USP7 inhibitors may lead to the discovery of highly promising USP7 inhibitors as anticancer drugs.