Beyond Docking: A Multitier Computational Pipeline for USP7 Inhibitor Optimization.

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Ubiquitin-specific protease 7 (USP7) is a critical enzyme in cellular processes like DNA repair and epigenetic regulation.
• USP7 plays a significant role in cancer progression, making it a key therapeutic target.

Purpose of the Study:

• To identify and optimize novel inhibitors of USP7 using a multi-tier computational strategy.
• To evaluate the anticancer potential and selectivity of the identified USP7 inhibitors.

Main Methods:

• Ligand-based virtual screening, molecular docking, and MD simulations were employed.
• MM/GBSA binding free energy calculations, binary QSAR modeling, and steered MD simulations were utilized.
• Cross-docking against USP family members assessed compound selectivity.

Main Results:

• High-affinity USP7 inhibitors were identified with docking scores below -8.0 kcal/mol.
• MD simulations and MM/GBSA calculations confirmed stability and interaction patterns.
• QSAR analysis predicted high therapeutic activity (normalized value > 0.5) for selected compounds.

Conclusions:

• The study successfully identified promising USP7 inhibitor candidates through comprehensive computational analysis.
• These compounds warrant further in vitro investigation for the development of advanced USP7-targeted cancer therapies.