Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.
J Phys Chem B. 2012 Mar 1;116(8):2605-14. doi: 10.1021/jp211768n. Epub 2012 Feb 14.
Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV) type 1 and 2 (HIV-1 and HIV-2). HIV-1 is observed worldwide while HIV-2 though prevalent in West Africa is persistently spreading to other parts of the world. An important target for AIDS treatment is the use of HIV protease (PR) inhibitors preventing the replication of the virus. In this work, the popular molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the effectiveness of the HIV-1 PR inhibitors darunavir, GRL-06579A, and GRL-98065 against HIV-2 and HIV-1 protease. The affinity of the inhibitors for both HIV-1 and HIV-2 PR decreases in the order GRL-06579A > darunavir > GRL-98065, in accordance with experimental data. On the other hand, our results show that all these inhibitors bind less strongly to HIV-2 than to HIV-1 protease, again in agreement with experimental findings. The decrease in binding affinity for HIV-2 relative to HIV-1 PR is found to arise from an increase in the energetic penalty from the desolvation of polar groups (DRV) or a decrease in the size of the electrostatic interactions between the inhibitor and the PR (GRL-06579A and GRL-98065). For GRL-98065, also a decrease in the magnitude of the van der Waals interactions contributes to the reduction in binding affinity. A detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of efficient inhibitors against HIV-2 protease.
获得性免疫缺陷综合征（AIDS）是由人类免疫缺陷病毒（HIV）1 型和 2 型（HIV-1 和 HIV-2）引起的。HIV-1 广泛存在于世界各地，而 HIV-2 虽然在西非流行，但仍持续向世界其他地区传播。艾滋病治疗的一个重要目标是使用 HIV 蛋白酶（PR）抑制剂来阻止病毒的复制。在这项工作中，我们使用了流行的分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法，研究了 HIV-1 PR 抑制剂 darunavir、GRL-06579A 和 GRL-98065 对 HIV-2 和 HIV-1 蛋白酶的抑制效果。抑制剂对 HIV-1 和 HIV-2 PR 的亲和力按 GRL-06579A>darunavir>GRL-98065 的顺序降低，这与实验数据一致。另一方面，我们的结果表明，所有这些抑制剂与 HIV-2 蛋白酶的结合强度都低于与 HIV-1 蛋白酶的结合强度，这再次与实验结果一致。与 HIV-1 PR 相比，与 HIV-2 PR 的结合亲和力降低是由于极性基团去溶剂化的能量惩罚（DRV）增加或抑制剂与 PR 之间的静电相互作用减小（GRL-06579A 和 GRL-98065）。对于 GRL-98065，范德华相互作用的大小减小也导致结合亲和力降低。深入了解控制结合和耐药性的分子力可能有助于设计针对 HIV-2 蛋白酶的高效抑制剂。
