虚拟筛选竞争性抑制NDRG3与L-Lactate结合的小分子研究  

Virtual Screening Competitive Inhibitors Against the Binding of NDRG3 and L-Lactate

作　　者：曹洪玉[1] 吴艳华[1] 周兴智 郑学仿[1] 蒋革[1] CAO Hongyu;WU Yanhua;ZHOU Xingzhi;ZHENG Xuefang;JIANG Ge(College of Life Science and Technology,Dalian University,Dalian 116622,China)

机构地区：[1]大连大学生命科学与技术学院,大连116622

出　　处：《华南师范大学学报（自然科学版）》2018年第3期58-64,共7页Journal of South China Normal University(Natural Science Edition)

基　　金：国家自然科学基金项目(21601025);大连市青年科技之星项目(2017RQ156);辽宁省自然科学基金指导计划项目(201602020)

摘　　要：竞争性抑制NDRG3(N-myc Downstream Regulated Gene 3)蛋白与L-Lactate结合可有效阻遏NDRG3介导的低氧反应.文中通过同源模建技术构建NDRG3蛋白的三维结构,并将L-Lactate对接到NDRG3蛋白的潜在活性位点中,发现L-Lactate主要通过与Asn133、Ala162、His163、His164、Ser235、Pro236及Ala237等氨基酸相互作用结合于NDRG3.对近3 000个化合物进行虚拟筛选,选择4种竞争性抑制最强的化合物作为参考分子分析相互作用关系.结果发现:部分化合物和不同氨基酸能够通过不同的作用力与NDRG3蛋白结合,占据NDRG3蛋白的活性位点,从而竞争性抑制L-Lactate与NDRG3蛋白结合.例如,它们能够与Lys139、Asp143、His163、Arg203产生静电作用;它们与His163形成π-π堆积作用;它们与Phe165、Ala237等产生疏水作用;它们与Asn133、Asp135、Gly140、Arg203、Ser235、Ala237等形成氢键作用.以上数据表明:这些化合物可能成为阻遏NDRG3介导的低氧反应及靶向治疗低氧诱导疾病的候选药物.Competitively inhibiting the binding of NDRG3（ N-myc Downstream Regulated Gene 3） and L-Lactate may be potentially a useful strategy for the repression of hypoxic response mediated by NDRG3. The three-dimensional（ 3 D） structure of NDRG3 is built by using homology modeling. Then L-Lactate is docked into NDRG3 and it is found that L-Lactate mainly binds with amino acid residues Asn133,Ala162,His163,His164,Ser235,Pro236 and Ala237 of NDRG3 in the potential active sites. Approximately 3,000 compounds have been virtually screened and the 4 top-ranked compounds are selected as reference molecules to analyze their interactions. The results show that some of them can form electrostatic force with Lys139,Asp143,His163 and Arg203,π-π stack with His163,hydrophobic effect with Phe165 and Ala237,and hydrogen bonds with Asn133,Asp135,Gly140,Arg203,Ser235 and Ala237 to occupy the active sites of NDRG3,thereby competitively inhibiting the binding of NDRG3 and L-Lactate. These compounds may be promising drug candidates for the suppression of hypoxic response mediated by NDRG3 and targeted therapy for hypoxia-induced diseases.

关 键 词：NDRG3 L-LACTATE 竞争性抑制剂 同源模建 分子对接 虚拟筛选 

分 类 号：O641.3[理学—物理化学]