Targeting Ubiquitin-Specific Protease 7 (USP7): A Pharmacophore-Guided Drug Repurposing and Physics-Based Molecular
Duaa Kanan1,2, Tarek Kanan1,2, Berna Dogan2,3
1Department of Internal Medicine, University of Illinois College of Medicine, Peoria, Illinois 61605, United States.
Abstract:
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.
Insights
Researchers identified 12 potential new cancer drugs by repurposing existing molecules to inhibit ubiquitin-specific protease 7 (USP7), a protein linked to poor patient survival and chemoresistance.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Ubiquitin-specific protease 7 (USP7) is crucial in regulating proteins involved in cancer development.
- USP7 overexpression is linked to reduced patient survival and increased chemoresistance in various cancers, including multiple myeloma.
- Targeting USP7 presents a promising strategy for novel cancer therapies.
Purpose of the Study:
- To identify novel USP7 inhibitors through a structure-based drug repurposing pipeline.
- To screen a library of FDA-approved and investigational small molecules for USP7 inhibitory potential.
- To prioritize and validate potential drug candidates for anticancer applications.
Main Methods:
- Utilized structure-based pharmacophore models derived from USP7-ligand crystal structures for screening.
- Employed molecular dynamics (MD) simulations (10 ns and 100 ns) and MM/GBSA calculations for binding energy assessment.
- Integrated quantitative structure-activity relationship (QSAR) modeling for cancer-specific activity prediction and ligand clustering.
Main Results:
- Screened 6654 small molecules, prioritizing hits based on pharmacophoric compatibility.
- Narrowed down candidates to 36 promising ligands after initial MD simulations and binding energy calculations.
- Identified 12 lead drug molecules, including carafiban, alnespirone, and troglitazone, with potential USP7 inhibitory activity.
Conclusions:
- The study successfully identified 12 potential USP7 inhibitors through a computational drug repurposing approach.
- These identified molecules represent promising lead candidates for further in vitro validation and development as anticancer drugs.
- This pipeline offers a strategy for discovering novel therapeutics targeting USP7 in oncology.
