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

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 (3D) structure of NDRG3 was built by using homology modeling for its crystal structure was not available. Then L-Lactate was docked into NDRG3, from which we knew it mainly bound 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 were selected as reference molecules to analyze their interaction relationships, which illustrated that some compounds could bind to NDRG3 protein by different forces with different amino acids, occupying the active sites of NDRG3, thereby competitively inhibiting the binding of NDRG3 and L-Lactate. They could form electrostatic force with Lys139, Asp143, His163, Arg203; π-π stack with His163; hydrophobic effect with Phe165, Ala237; hydrogen bonds with Asn133, Asp135, Gly140, Arg203, Ser235 and Ala237. These compounds may be promising drug candidates for the suppression of hypoxic response mediated by NDRG3 and targeted therapy for hypoxia-induced diseases