A Promising Target for Cancer Treatment

Unraveling the Crucial Role of USP7 in Cancer

Cancer remains a significant global health challenge, with over 10 million deaths attributed to it in 2020 alone. The complexity and heterogeneity of cancer pose challenges to effective treatment, necessitating continued efforts in therapeutic development. One promising target in this pursuit is the ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme implicated in various cellular processes, including DNA repair, cell cycle regulation, and immune response modulation.

USP7 has emerged as an attractive therapeutic target for cancer management due to its involvement in several critical pathways. At basal expression levels, USP7 stabilizes the p53 protein, a crucial tumor suppressor. However, the overexpression of USP7 leads to the deubiquitination of MDM2, a negative regulator of p53, resulting in p53 degradation and promoting pro-tumorigenic roles. Additionally, increased USP7 levels have been linked to immunosuppressive functions, further contributing to cancer progression.

Targeting the Allosteric Site of USP7: A Promising Approach

Natively, USP7 exists in an inactive state and is activated by the binding of ubiquitin to an allosteric site within its catalytic domain. This allosteric activation involves dynamic changes in two critical loops, the blocking loop-1 and the switching loop, which play a crucial role in regulating the enzyme’s activity. Inhibiting the allosteric site of USP7 to prevent the binding of ubiquitin is a viable strategy for cancer drug discovery.

Computational Approaches Unveil Potential Allosteric Site Modulators

In this comprehensive study, researchers employed a range of advanced computational techniques to identify and evaluate potential allosteric site modulators of USP7. The researchers first retrieved an anticancer compound library and optimized the structures using the OPLS4 force field. They then obtained the tertiary structure of USP7 from the Protein Data Bank and prepared it for molecular docking simulations.

The researchers conducted virtual screening of the compound library against the USP7 active site, followed by binding free energy calculations using the Prime MMGBSA post-docking protocol. This approach identified eight compounds from the library with significantly higher binding affinities for the USP7 allosteric site compared to the reference compound, P217564, a selective irreversible second-generation inhibitor of USP7.

Evaluating the Drug-like Properties and Pharmacokinetic Profiles

The researchers further assessed the drug-like properties and pharmacokinetic profiles of the top four compounds with the highest binding affinities. All the hit compounds were found to possess favorable drug-like characteristics, including molecular weights less than 500 Da, appropriate numbers of hydrogen bond donors and acceptors, and desirable octanol-water partition coefficients (logP values), indicating their potential for oral drug development.

Additionally, the compounds exhibited high human intestinal absorption and were predicted to have good pharmacokinetic properties, such as low toxicity and the ability to be metabolized by phase I and II enzymes. These findings suggest that the identified compounds have the potential to be effective and well-tolerated anticancer agents.

Molecular Dynamics Simulations Confirm Stability and Interactions

To further investigate the dynamic behavior of USP7 upon the binding of the hit compounds, the researchers conducted molecular dynamics simulations for 100 nanoseconds. The results revealed that the binding of the hit compounds led to stable interactions with key residues within the USP7 allosteric site, confirming the stability of the protein-ligand complexes.

The analysis of the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration, and hydrogen bond formation provided insights into the conformational changes and interactions between USP7 and the hit compounds. These findings corroborated the computational predictions and strengthened the potential of the identified compounds as promising allosteric modulators of USP7.

Implications and Future Directions

This study’s findings highlight the potential of targeting the allosteric site of USP7 as a viable approach for cancer drug discovery. The researchers identified four compounds with high binding affinities, favorable drug-like properties, and stable interactions with the USP7 allosteric site, making them worthy of further evaluation and optimization.

The study’s comprehensive computational approach, which combined molecular modeling, cheminformatics, and molecular dynamics simulations, provides a robust framework for the discovery of novel allosteric modulators of USP7 and other therapeutic targets. These insights pave the way for further experimental validation and the development of effective anticancer therapies that target the USP7 enzyme.

As the research continues, the identified compounds may undergo additional in vitro and in vivo studies to assess their efficacy, safety, and potential for clinical translation. Exploring the structural basis of the protein-ligand interactions and investigating the compounds’ impact on downstream signaling pathways could also yield valuable information to guide the development of more potent and selective USP7 inhibitors.

In conclusion, this study’s findings offer a promising avenue for the discovery of new cancer treatments by targeting the allosteric site of the critical enzyme, USP7. The computational approaches employed have yielded valuable insights and identified potential lead compounds that warrant further investigation, ultimately contributing to the ongoing efforts to overcome the challenges of cancer.

Author credit: This article is based on research by Olayinka Abraham Ojedele, Haruna Isiyaku Umar, Soukayna baammi, Amira Metouekel, Atrsaw Asrat Mengistie, Yousef A. Bin Jardan, Gamal A. Shazly, Omoboyede Victor.

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