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

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.