Molecular dynamics simulation reveals the possible druggable hot-spots of USP7

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Ubiquitin Specific Protease 7 (USP7) plays a critical role in oncogenic pathways and immune-oncology.
• Developing USP7 inhibitors is of significant interest, but challenges remain in identifying binding sites and mechanisms of action for deubiquitinase (DUB) inhibitors.
• USP7 exhibits plasticity, undergoing conformational changes that influence its regulation.

Purpose of the Study:

• To identify the most likely binding site of the potent USP7 inhibitor P5091.
• To elucidate the mechanism of USP7 inhibition through computational studies.
• To explore novel allosteric binding sites for structure-guided inhibitor design.

Main Methods:

• Extensive computational studies, including molecular dynamics simulations.
• Detailed quantitative analysis of USP7 dynamics.
• Investigated inhibitor-dependent and inhibitor-independent binding modes.

Main Results:

• A cryptic allosteric binding site near the catalytic center of the inactive USP7 state was identified.
• This allosteric site is partially absent in the active USP7 state.
• Two additional novel binding sites were revealed through simulations.

Conclusions:

• The findings demonstrate the tractability and druggability of USP7.
• The identified allosteric sites provide new avenues for rational, structure-guided design of USP7-specific inhibitors.
• This work facilitates the development of targeted therapies in oncology and immunology.