ABSTRACT

HIV-1 protease (PR) is thought to be efficient targets of anti-AIDS drug design. Molecular dynamics (MD) simulations and multiple post-processing analysis technologies were applied to decipher molecular mechanism underlying binding of three drugs Lopinavir (LPV), Nelfinavir (NFV) and Atazanavir (ATV) to the PR. Binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) suggest that compensation between binding enthalpy and entropy plays a vital role in binding of drugs to PR. Dynamics analyses show that binding of LPV, NFV and ATV highly affects structural flexibility, motion modes and dynamics behaviour of the PR, especially for two flaps. Computational alanine scanning and interaction network analysis verify that although three drugs have structural difference, they share similar binding modes to the PR and common interaction clusters with the PR. The current findings also confirm that residues located interaction clusters, such as Asp25/Asp25ʹ, Gly27/Gly27ʹ, Ala28/Ala28ʹ, Asp29, Ile47/Ile47ʹ, Gly49/Gly49ʹ, Ile50/Ile50ʹ, Val82/Val82ʹ and Ile84/Ile84, can be used as efficient targets of clinically available inhibitors towards the PR.

摘要

HIV-1 蛋白酶 (PR) 被认为是抗艾滋病药物设计的有效目标。分子动力学 (MD) 模拟和多种后处理分析技术被应用于破译三种药物洛匹那韦 (LPV)、奈非那韦 (NFV) 和阿扎那韦 (ATV) 与 PR 结合的分子机制。通过分子力学广义玻恩表面积 (MM-GBSA) 计算的结合自由能表明结合焓和熵之间的补偿在药物与 PR 的结合中起着至关重要的作用。动力学分析表明，LPV、NFV 和 ATV 的结合高度影响 PR 的结构灵活性、运动模式和动力学行为，尤其是对于两个襟翼。计算丙氨酸扫描和相互作用网络分析证实，虽然三种药物存在结构差异，它们与 PR 共享相似的绑定模式以及与 PR 的通用交互集群。目前的研究结果还证实了残基位于相互作用簇中，例如 Asp25/Asp25ʹ、Gly27/Gly27ʹ、Ala28/Ala28ʹ、Asp29、Ile47/Ile47ʹ、Gly49/Gly49、Ile50/Ile50ʹ、Val82/Ile5ʹ、Val82/Ile4ʹIle82ʹIle4作为针对 PR 的临床可用抑制剂的有效靶点。