College of Life Sciences and Bioengineering, Beijing University of Technology, Beijing 100124, China.
J Biomol Struct Dyn. 2011 Oct;29(2):311-23. doi: 10.1080/07391102.2011.10507387.
Integrase is an essential enzyme in the life cycle of Human immunoficiency virus type 1 (HIV-1) and also an important target for designing integrase inhibitors. In this paper, the binding modes between the wild type integrase core domain (ICD) and the W131A mutant ICD with the benzoic acid derivative--D77 were investigated using the molecular docking combined with molecular dynamics (MD) simulations. The result of MD simulations showed that the W131A substitution affected the flexibility of the region 150-167 in both the monomer A and B of the mutant type ICD. In principle, D77 interacted with the residues around the Lens Epithelium-Derived Growth Factor (LEDGF/p75) binding site which is nearby the HIV-1 integrase dimer interface. However, the specific binding modes for D77-wild type integrase and D77-mutant integrase systems are various. According to the binding mode of D77 with the wild type ICD, D77 can effectively intervene with the binding of LEDGF/p75 to integrase due to a steric hindrance effect around the LEDGF/p75 binding site. In addition, we found that D77 might also affect its inhibitory action by reducing the flexibility of the region 150-167 of integrase. Through energy decomposition calculated with the Molecular Mechanics Generalized Born Surface Area approach to estimate the binding affinity, it seems likely that W131 and E170 are indispensable for the ligand binding, as characterized by the largest binding affinity. All the above results are consistent with the experimental data, providing us with some helpful information not only for the understanding of the mechanism of this kind of inhibitor but also for the rational drug design.
整合酶是人类免疫缺陷病毒 1 型（HIV-1）生命周期中的一种必需酶，也是设计整合酶抑制剂的重要靶点。在本文中，我们使用分子对接结合分子动力学（MD）模拟研究了野生型整合酶核心结构域（ICD）与苯甲酸盐衍生物 D77 结合的 W131A 突变 ICD 的结合模式。MD 模拟的结果表明，W131A 取代影响了突变型 ICD 单体 A 和 B 中 150-167 区域的灵活性。原则上，D77 与 Lens Epithelium-Derived Growth Factor（LEDGF/p75）结合位点附近的 HIV-1 整合酶二聚体界面的残基相互作用。然而，D77 与野生型整合酶和 D77 突变型整合酶系统的具体结合模式不同。根据 D77 与野生型 ICD 的结合模式，D77 可以通过在 LEDGF/p75 结合位点周围产生空间位阻效应，有效干扰 LEDGF/p75 与整合酶的结合。此外，我们发现 D77 可能通过降低整合酶 150-167 区域的灵活性来影响其抑制作用。通过使用分子力学广义 Born 表面面积方法计算能量分解来估计结合亲和力，似乎 W131 和 E170 对配体结合是不可或缺的，这表现为最大的结合亲和力。所有上述结果都与实验数据一致，为我们提供了一些有价值的信息，不仅有助于理解这种抑制剂的作用机制，也有助于合理的药物设计。
