Liu Ming, Cong Xiao Jing, Li Ping, Tan Jian Jun, Chen Wei Zu, Wang Cun Xin
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
Biopolymers. 2009 Sep;91(9):700-9. doi: 10.1002/bip.21211.
Human immunodeficiency virus type 1 integrase (IN) is an essential enzyme in the life cycle of this virus and also an important target for the study of anti-HIV drugs. In this work, the binding modes of the wild type IN core domain and the two mutants, that is, W132G and C130S, with the 4-hydroxycoumarin compound NSC158393 were evaluated by using the "relaxed complex" molecular docking approach combined with molecular dynamics (MD) simulations. Based on the monomer MD simulations, both of the two substitutions affect not only the stability of the 128-136 peptides, but also the flexibility of the functional 140s loop. In principle, NSC158393 binds the 128-136 peptides of IN; however, the specific binding modes for the three systems are various. According to the binding mode of NSC158393 with WT, NSC158393 can effectively interfere with the stability of the IN dimer by causing a steric hindrance around the monomer interface. Additionally, through the comparative analysis of the MD trajectories of the wild type IN and the IN-NSC158393 complex, we found that NSC15893 may also exert its inhibitory function by diminishing the mobility of the function loop of IN. Three key binding residues, that is, W131, K136, and G134, were discovered by energy decomposition calculated with the Molecular Mechanics Generalized Born Surface Area method. Characterized by the largest binding affinity, W131 is likely to be indispensable for the ligand binding. All the above results are consistent with experiment data, providing us some helpful information for understanding the mechanism of the coumarin-based inhibitors.
人类免疫缺陷病毒1型整合酶（IN）是该病毒生命周期中的一种必需酶，也是抗HIV药物研究的重要靶点。在本研究中，采用“松弛复合物”分子对接方法结合分子动力学（MD）模拟，评估了野生型IN核心结构域以及两个突变体W132G和C130S与4-羟基香豆素化合物NSC158393的结合模式。基于单体MD模拟，这两个取代不仅影响128 - 136肽段的稳定性，还影响功能性140s环的灵活性。原则上，NSC158393与IN的128 - 136肽段结合；然而，这三种体系的具体结合模式各不相同。根据NSC158393与野生型（WT）的结合模式，NSC158393可通过在单体界面周围造成空间位阻，有效干扰IN二聚体的稳定性。此外，通过对野生型IN和IN - NSC158393复合物的MD轨迹进行比较分析，我们发现NSC15893还可能通过降低IN功能环的流动性来发挥其抑制作用。利用分子力学广义玻恩表面积方法进行能量分解，发现了三个关键结合残基，即W131、K136和G134。以最大结合亲和力为特征，W131可能是配体结合所必需的。所有上述结果与实验数据一致，为我们理解香豆素类抑制剂的作用机制提供了一些有用信息。
