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Targeting the TRIM28-EZH2 Protein-Protein Interface With Cysteine-Reactive Covalent Inhibitors: A Computational
Ibrahim Oluwatobi Kehinde1, Vuyisa Mzozoyana2, Sizwe J Zamisa2
1Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Abstract:
Aberrant protein-protein interactions (PPIs) play crucial roles in cancer progression by driving transcriptional repression and epigenetic silencing. Among these, the TRIM28-EZH2 interaction is central to maintaining repressive chromatin states that promote tumorigenesis. In this study, we modeled the TRIM28-EZH2 complex using protein-protein docking, revealing a stable interface dominated by the RBCC domain of TRIM28 and the PRC2 catalytic domain of EZH2. A cysteine-focused covalent inhibitor library was screened to identify small molecules capable of targeting reactive cysteines at the interface. Four lead compounds were identified, with compound C87 exhibiting the most favorable binding free energy (ΔGbind = -57.2 kcal/mol) and stable interactions throughout molecular dynamics simulations. These findings highlight the potential of covalent inhibition as a novel strategy to disrupt oncogenic TRIM28-EZH2 complexes and restore tumor suppressor gene expression.
Insights
Aberrant protein-protein interactions drive cancer. This study identifies covalent inhibitors targeting the TRIM28-EZH2 complex, a key driver of tumor progression, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant protein-protein interactions (PPIs) are critical in cancer, promoting tumor growth via transcriptional repression and epigenetic silencing.
- The TRIM28-EZH2 interaction maintains repressive chromatin, contributing to tumorigenesis.
Purpose of the Study:
- To model the TRIM28-EZH2 complex and identify small molecules targeting their interface.
- To explore covalent inhibition as a strategy against oncogenic PPIs.
Main Methods:
- Protein-protein docking was used to model the TRIM28-EZH2 complex structure.
- A cysteine-focused covalent inhibitor library was screened.
- Molecular dynamics simulations assessed compound stability and binding.
Main Results:
- A stable interface between TRIM28's RBCC domain and EZH2's PRC2 domain was identified.
- Four lead covalent inhibitors were discovered, with compound C87 showing the best binding free energy (-57.2 kcal/mol).
- Compound C87 demonstrated stable interactions during simulations.
Conclusions:
- Covalent inhibition is a promising strategy to disrupt the oncogenic TRIM28-EZH2 complex.
- Targeting this PPI could restore tumor suppressor gene expression and inhibit cancer progression.
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