Rational Computational Workflow for Structure-Guided Discovery of a Novel USP7 Inhibitor

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Structural Biology

Background:

• Rational drug design relies on computational methods to identify potent chemotypes targeting specific structural determinants.
• Ubiquitin-specific protease 7 (USP7) is a validated target in cancer therapy.

Purpose of the Study:

• To implement a computational workflow for identifying novel USP7 inhibitors.
• To characterize the binding mode and mechanism of action of a promising hit compound.

Main Methods:

• Integrated computational approaches combining cocrystal pose analysis and molecular dynamics simulations.
• In vitro screening of diverse chemical scaffolds across six cancer cell lines.
• Biophysical binding assays and enzymatic assays to confirm USP7 inhibition.

Main Results:

• Identification of benzothiazole compound M15 as a potent anticancer agent against USP7.
• M15 demonstrated dose-dependent reduction in cancer cell viability and confirmed binding to USP7.
• Structural analysis revealed a distinct binding mode of M15, occupying both BL1 and an allosteric checkpoint.

Conclusions:

• The study presents a robust computational method for discovering and characterizing novel inhibitor scaffolds.
• M15 represents a promising lead compound for USP7-targeted cancer therapy.
• The findings advance the understanding of USP7 inhibition and highlight novel druggable sites.