Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that is overexpressed in many cancers. Numerous EZH2 inhibitors have been developed as anticancer agents, but recent studies have also focused on protein–protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2 as a novel drug discovery target. Because EED indirectly enhances EZH2 enzymatic activity, EED-EZH2 PPI inhibitors suppress the methyltransferase activity and inhibit cancer growth. By contrast to the numerous promising EZH2 inhibitors, there are a paucity of EED-EZH2 PPI inhibitors reported in the literature. Here, we aimed to discover novel EED-EZH2 PPI inhibitors by first identifying possible binders of EED using an in-house knowledge-based in silico fragment mapping method. Next, 3D pharmacophore models were constructed from the arrangement pattern of the potential binders mapped onto the EED surface. In all, 16 compounds were selected by 3D pharmacophore-based virtual screening followed by docking-based virtual screening. In vitro evaluation revealed that five of these compounds exhibited inhibitory activities. This study has provided structural insights into the discovery and the molecular design of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method.

zeste 同源物 2 (EZH2) 增强子是一种组蛋白赖氨酸甲基转移酶，在许多癌症中过度表达。许多 EZH2 抑制剂已被开发为抗癌剂，但最近的研究还集中在胚胎外胚层发育 (EED) 和 EZH2 之间的蛋白质-蛋白质相互作用 (PPI) 作为新的药物发现靶点。由于 EED 间接增强 EZH2 酶活性，EED-EZH2 PPI 抑制剂抑制甲基转移酶活性并抑制癌症生长。与众多有前景的 EZH2 抑制剂相比，文献中报道的 EED-EZH2 PPI 抑制剂很少。在这里，我们旨在通过首先使用基于内部知识的计算机片段映射方法识别 EED 的可能结合物来发现新型 EED-EZH2 PPI 抑制剂。下一个，3D 药效团模型是根据映射到 EED 表面的潜在结合剂的排列模式构建的。通过基于 3D 药效团的虚拟筛选和基于对接的虚拟筛选，总共选择了 16 种化合物。体外评估表明，这些化合物中有五种表现出抑制活性。这项研究使用计算机片段作图方法为新型 EED-EZH2 PPI 抑制剂的发现和分子设计提供了结构见解。