Druggability assessments of small peptides as protein-protein interaction inhibitors targeting EED-EZH2 binding...

Histone methylation is a key epigenetic modification involved in gene silencing and plays a crucial role in chromatin remodelling. Polycomb repressive complex 2 (PRC2), a histone-modifying complex, has been implicated in various diseases, including cancers and genetic disorders. Since PRC2 is a multi-protein complex, the structural interactions among its component proteins are essential for its proper function. Consequently, inhibiting the formation of this complex is considered an effective strategy to block PRC2 activity. This research evaluated small peptides as protein-protein interaction (PPI) inhibitors to disrupt the binding between two key PRC2 components, Embryonic Ectoderm Development (EED) and Enhancer of Zeste Homolog 2 (EZH2), using computational approaches. Initially, pharmacophore models were generated based on the structural features of EED and EZH2, followed by pharmacophore-based virtual screening to identify tetra-peptide candidates from a library of 160,000 compounds. Molecular docking, molecular dynamics simulations, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, binding energy estimation, toxicity prediction, and membrane permeability predictions were employed to filter the most promising leads. The study identified several tetra-peptides, including WSYN, HQHE, WVYS, HYEN, WHAE, IPWP, KNNQ, CGKQ, and CIHN, as strong EED-EZH2 PPI inhibitors. Molecular docking, MD simulations, and binding energy analysis revealed stable and effective binding of the peptides to the EZH2-interacting region of EED, further supported by PCA analysis. Their non-toxic, drug-like properties and membrane permeability highlight their strong potential as lead candidates for developing EED-EZH2 interaction inhibitors.