Binding Modes of Small-Molecule Inhibitors to the EED Pocket of PRC2
Dading Huang1, Shuaizhen Tian1, Yifei Qi1,2
1School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
Abstract:
Polycomb Polycomb repressive complex 2 (PRC2) plays a key role in silencing epigenetic gene through trimethylation of lysine 27 on histone 3 (H3K27). Dysregulations of PRC2 caused by overexpression and mutations of the core subunits of PRC2 have been implicated in many cancers. The core subunits EZH1/2 are histone-lysine N-methyltransferases that function as the enzymatic component of PRC2. While the core subunit EED is a scaffolding protein to support EZH1/2 and binds JARID2K116me3/H3K27me3 to enhance the enzymatic activity of PRC2 through allosteric activation. Recently, several small molecules that compete with JARI2K116me3 and H3K27me3 have been reported. These molecules selectively bind to the JARID2K116me3/H3K27me3-binding pocket of EED, thereby preventing the allosteric regulation of PRC2. These first-in-class PRC2 inhibitors show robust suppression in DLBCL cell lines, demonstrating anticancer drugs that target the EED subunit of PRC2 are viable. In this study, we used the recently developed MM/GBSA_IE and the alanine scanning method to analyze the hot spots in EED/inhibitor interactions. The analysis of these hot and warm spots helps us to understand the fundamental differences between inhibitors. Our results give a quantitative explanation on why the binding affinities of EED/A-395 interactions are stronger than that of EED/EED226 while their binding modes are similar and provide valuable insights for rational design of novel EED inhibitors.
Insights
Polycomb repressive complex 2 (PRC2) inhibitors targeting the EED subunit show promise as cancer drugs. Molecular dynamics simulations reveal key interactions, guiding the design of more effective EED inhibitors for cancer therapy.
Area of Science:
- Epigenetics
- Molecular Biology
- Pharmacology
Background:
- Polycomb repressive complex 2 (PRC2) epigenetically silences genes via histone H3 lysine 27 trimethylation (H3K27me3).
- PRC2 dysregulation is linked to various cancers, with core subunits EZH1/2 and EED being crucial.
- EED acts as a scaffold, binding JARID2K116me3/H3K27me3 to allosterically activate PRC2's enzymatic function.
Purpose of the Study:
- To analyze critical interaction 'hot spots' between the EED subunit and PRC2 inhibitors using computational methods.
- To understand the molecular basis for differential binding affinities between EED and various inhibitors.
- To provide insights for the rational design of novel and potent EED inhibitors for cancer treatment.
Main Methods:
- Molecular mechanics with generalized Born surface area (MM/GBSA_IE) calculations.
- Alanine scanning simulations to identify key residues in EED/inhibitor interactions.
- Comparative analysis of binding modes and affinities for different inhibitors.
Main Results:
- Identified specific hot and warm spots in EED/inhibitor interactions, differentiating inhibitor efficacy.
- Provided a quantitative explanation for stronger binding affinity of EED/A-395 compared to EED/EED226, despite similar binding modes.
- Demonstrated the potential of targeting the EED subunit for developing effective anticancer therapeutics.
Conclusions:
- Targeting the EED subunit of PRC2 with small molecule inhibitors is a viable anticancer strategy.
- Computational analysis of EED/inhibitor interactions provides crucial insights for drug design.
- This study facilitates the development of next-generation EED inhibitors with improved potency and selectivity.
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