Structure-based virtual screening of novel USP5 inhibitors targeting the zinc finger ubiquitin-binding domain
Tianhao Wang1, Jianbo Tong2, Xing Zhang1
1Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
Abstract:
The equilibrium of cellular protein levels is pivotal for maintaining normal physiological functions. USP5 belongs to the deubiquitination enzyme (DUBs) family, controlling protein degradation and preserving cellular protein homeostasis. Aberrant expression of USP5 is implicated in a variety of diseases, including cancer, neurodegenerative diseases, and inflammatory diseases. In this paper, a multi-level virtual screening (VS) approach was employed to target the zinc finger ubiquitin-binding domain (ZnF-UBD) of USP5, leading to the identification of a highly promising candidate compound 0456-0049. Molecular dynamics (MD) simulations were then employed to assess the stability of complex binding and predict hotspot residues in interactions. The results indicated that the candidate stably binds to the ZnF-UBD of USP5 through crucial interactions with residues ARG221, TRP209, GLY220, ASN207, TYR261, TYR259, and MET266. Binding free energy calculations, along with umbrella sampling (US) simulations, underscored a superior binding affinity of the candidate relative to known inhibitors. Moreover, US simulations revealed conformational changes of USP5 during ligand dissociation. These insights provide a valuable foundation for the development of novel inhibitors targeting USP5.
Insights
Researchers identified a promising compound targeting USP5, a key enzyme in cellular protein balance implicated in diseases like cancer. This discovery paves the way for developing new USP5 inhibitors to combat various health conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cellular protein homeostasis is crucial for physiological functions.
- USP5, a deubiquitinating enzyme (DUB), regulates protein degradation and is implicated in diseases like cancer and neurodegenerative disorders.
- Targeting USP5 offers a therapeutic strategy for various pathologies.
Purpose of the Study:
- To identify novel inhibitors targeting the zinc finger ubiquitin-binding domain (ZnF-UBD) of USP5.
- To evaluate the binding affinity and stability of a candidate compound.
- To provide insights for the development of new USP5-targeted therapeutics.
Main Methods:
- Multi-level virtual screening (VS) to identify potential inhibitors.
- Molecular dynamics (MD) simulations to assess binding stability and interactions.
- Binding free energy calculations and umbrella sampling (US) simulations to quantify binding affinity and conformational changes.
Main Results:
- A promising candidate compound, 0456-0049, was identified targeting USP5's ZnF-UBD.
- MD simulations confirmed stable binding of the compound, highlighting key interacting residues (ARG221, TRP209, GLY220, ASN207, TYR261, TYR259, MET266).
- Binding free energy and US simulations demonstrated superior affinity compared to known inhibitors and revealed USP5 conformational changes during ligand dissociation.
Conclusions:
- The identified compound exhibits strong binding affinity and stability to USP5.
- These findings provide a solid foundation for designing novel USP5 inhibitors.
- This research contributes to the development of potential treatments for USP5-related diseases.
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