Study on the interactions between diketo-acid inhibitors and prototype foamy virus integrase-DNA complex via molecular docking and comparative molecular dynamics simulation methods
Study on the interactions between diketo-acid inhibitors and prototype foamy virus integrase-DNA complex via molecular docking and comparative molecular dynamics simulation methods
复制标题
通过分子对接和比较分子动力学模拟方法研究二酮酸抑制剂与原型泡沫病毒整合酶-DNA复合物之间的相互作用
DOI：
10.1080/07391102.2012.709458
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Chang, Shan
中科院分区：
文献类型：
--
作者：
Hu, Jian-Ping;He, Hong-Qiu;Chang, Shan
人类免疫缺陷病毒1型（HIV-1）整合酶（IN）是抗获得性免疫缺陷病（AIDS）治疗的重要药物靶点，二酮酸（DKA）抑制剂是HIV-1 IN的有效选择性抑制剂。由于缺乏包括HIV-1 IN与其底物病毒DNA之间的详细相互作用的三维结构，药物设计和筛选平台仍然不完整和不足。此外，DKA抑制剂与HIV-1 IN的作用机制还不清楚。鉴于原型泡沫病毒（PFV）IN与HIV-1 IN结构高度同源，我们以PFV IN作为HIV-1 IN的替代模型，研究雷特格韦（RLV）的抑制机制及其与一系列DKA抑制剂的结合模式。首先，PFV IN，IN-RLV，IN-DNA和IN-DNA-RLV系统的分子动力学模拟进行了10 ns。通过整体动力学行为、催化环构象分布和氢键网络分析，探讨了RLV与PFV IN的相互作用及其抑制机制。结果表明，RLV与IN和病毒DNA的协同作用使IN催化环区的柔性略有降低，但明显限制了病毒DNA CA端的移动性，可能导致IN抑制活性的部分丧失。然后，我们将一系列DKA抑制剂与PFV IN-DNA受体对接，得到IN-DNA-抑制剂复合物。PFV IN-DNA与DKA抑制剂的对接结果与HIV-1 IN的对接结果一致，证明PFV IN-DNA用于抗艾滋病药物筛选的可靠性。本研究为进一步弄清有关理论问题和设计基于IN结构的抗艾滋病药物提供了理论依据。
Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an important drug target for anti-acquired immune deficiency disease (AIDS) treatment and diketo-acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN. Due to lack of three-dimensional structures including detail interactions between HIV-1 IN and its substrate viral DNA, the drug design and screening platform remains incompleteness and deficient. In addition, the action mechanism of DKA inhibitors with HIV-1 IN is not well understood. In view of the high homology between the structure of prototype foamy virus (PFV) IN and that of HIV-1 IN, we used PFV IN as a surrogate model for HIV-1 IN to investigate the inhibitory mechanism of raltegravir (RLV) and the binding modes with a series of DKA inhibitors. Firstly, molecular dynamics simulations of PFV IN, IN-RLV, IN-DNA, and IN-DNA-RLV systems were performed for 10 ns each. The interactions and inhibitory mechanism of RLV to PFV IN were explored through overall dynamics behaviors, catalytic loop conformation distribution, and hydrogen bond network analysis. The results show that the coordinated interactions of RLV with IN and viral DNA slightly reduce the flexibility of catalytic loop region of IN, and remarkably restrict the mobility of the CA end of viral DNA, which may lead to the partial loss of the inhibitory activity of IN. Then, we docked a series of DKA inhibitors into PFV IN-DNA receptor and obtained the IN-DNA-inhibitor complexes. The docking results between PFV IN-DNA and DKA inhibitors agree well with the corresponding complex of HIV-1 IN, which proves the dependability of PFV IN-DNA used for the anti-AIDS drug screening. Our study may help to make clear some theoretical questions and to design anti-AIDS drug based on the structure of IN.