Zhang Chongqian, Du Chunmiao, Feng Zhiwei, Zhu Jingyu, Li Youyong
Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China.
Chem Biol Drug Des. 2015 Feb;85(2):119-36. doi: 10.1111/cbdd.12377. Epub 2014 Jul 10.
CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.
CXCR4作为HIV-1锚定到哺乳动物细胞膜的共受体与CCR5发挥关键作用，并且与癌症转移和炎症有关。在当前工作中，我们使用HQSAR、对接和分子动力学（MD）模拟研究了AMD11070衍生物及其他CXCR4抑制剂的结构与活性之间的关系。我们得到了一个HQSAR模型（q(2)=0.779），并且HQSAR结果表明AMD11070显示出高抗逆转录病毒活性。由于HQSAR仅提供二维信息，我们进行对接和MD以研究It1t、AMD3100和AMD3465与CXCR4的相互作用。我们的结果表明，结合受到两个关键残基Asp97和Glu288的影响。AMD11070的丁胺部分有助于其高抗逆转录病毒活性。没有丁胺部分，(2,7a-二氢-1H-苯并咪唑-2-基甲基)-甲基-(5,6,7,8-四氢喹啉-8-基)-胺（化合物5a）显示出低抗逆转录病毒活性。我们的结果提供了关于抑制剂与CXCR4之间相互作用的结构细节，这对于CXCR4的合理药物设计是有用的。
