表观遗传修饰对基因转录的调控与许多重要的生理及病理过程密切相关，如细胞分化发育、肿瘤发生发展等。在人类许多恶性疾病中均存在表观修饰酶的基因突变。本项目拟选取几种与疾病密切相关的组蛋白甲基化酶、乙酰化酶及去乙酰化酶为研究靶标，测定它们与底物、配体及其他调节蛋白复合体的三维结构，解析调节这些酶活性的分子机制。开展结构指导下的理性药物设计研究，结合计算机虚拟筛选以及多轮构效关系（SAR）研究，优化得到特异干预酶活性的小分子抑制剂，为我国在表观遗传靶点的药物设计研究领域开拓新的思路和方向。

Epigenetic regulations of gene expression are important for many physiological and pathological processes, such as cell differentiation and tumorigenesis. Genetic mutations of epigenetic factors have been found in many human malignant diseases. This project aims to determine the structures of histone modification enzymes in complex with their substrates, ligands and interacting proteins. By studying the structural and functional relationship, to determine the molecular mechanism governing the activity regulation of these enzymes, followed by rational drug design and virtual screening based on these structures. Small molecule inhibitors will be evaluated and optimized by iterative Structure-Activity Relationship (SAR) analyses. These results will provide insights into the design and development of new epigenetic drugs.