DJ-1蛋白抑制剂的分子设计、构效关系、生物活性测试及生物学作用机制研究

项目名称： DJ-1蛋白抑制剂的分子设计、构效关系、生物活性测试及生物学作用机制研究

项目编号： No.81473135

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈建忠

作者单位： 浙江大学

项目金额： 80万元

中文摘要： DJ-1蛋白以二聚体参与生理功能的半胱氨酸蛋白酶。作为癌基因蛋白，DJ-1的高表达与多种肿瘤发生发展密切相关，但目前尚未见其抑制剂报导并研究抗肿瘤活性。本项目以先期发现的抑制DJ-1二聚化的化合物为先导，运用合理药物设计方法，结合药物化学知识，通过骨架越迁、基团修饰、分子形态比较和配体与DJ-1相互作用模拟等设计化合物，测定抑制DJ-1二聚化活性、结合常数和抗肿瘤活性，开展构效关系研究，建立3D-QSAR模型分析分子电性和立体效应对活性的影响。基于定点突变和共结晶研究化合物与DJ-1的结合模式及相应关键氨基酸，结合NMR溶液稳定结构分析分子柔性对活性的影响，指导化合物的设计与优化。并通过研究DJ-1抑制剂抑制DJ-1生物活性对细胞周期信号通路的调节探索其生物学作用机制，阐明DJ-1抑制剂抑制DJ-1生物活性引起肿瘤细胞凋亡的理论依据，为DJ-1蛋白成为抗肿瘤药物研究新作用靶点提供理论基础。

中文关键词： DJ-1抑制剂；药物分子设计；构效关系；结构生物学；抗肿瘤作用机制

英文摘要： DJ-1 is a dimer and involves in multi physiological processes. As an oncogene,DJ-1 has been reported to be close association with the development of multiple cancers. In the current proposal, we will apply our previously discovered compounds, which can inhibit dimerization of DJ-1, as lead compounds for structure optimization and structure-activity relationship study. Based on the knowledge of rational drug design and medicinal chemistry, the work will be performed with scaffold hopping, substituents modification, molecular shape similarity, and MD simulations of ligand-protein interaction for further improving the design of compound. We also will establish 3D-QSAR model for refining drug design. The co-crystallization and site mutagenesis will be carried out to study the interaction mode of compound binding to DJ-1, and the corresponding key residues in the binding pocket of DJ-1 for further drug design. Meanwhile, biological activity mechanism will be explored by the DJ-1 inhibitor's effects on the cellular signal pathway. Based on the study results, we will confirm that DJ-1 can be a new target for the development of anti-tumor drug.

英文关键词： Inhibitor;Drug Design;SAR;strutural biology;anti-cancer mechanism