Origin of Decrease in Potency of Darunavir and Two Related Antiviral Inhibitors against HIV-2 Compared to HIV-1 Protease
Origin of Decrease in Potency of Darunavir and Two Related Antiviral Inhibitors against HIV-2 Compared to HIV-1 Protease
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DOI：
10.1021/jp211768n
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发表时间：
2012-03-01
影响因子：
3.3
通讯作者：
Knecht, Volker
中科院分区：
文献类型：
--
作者：
Kar, Parimal;Knecht, Volker
获得性免疫缺陷综合征（ALDS）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在全世界都有发现，而HIV-2虽然在西非流行，但正在持续向世界其他地区蔓延。艾滋病治疗的一个重要目标是使用HIV蛋白酶（PR）抑制剂预防病毒复制。在这项工作中，流行的分子力学Poisson-Boltzmann表面积（MM-PBSA）方法已被用于研究HIV-1 PR抑制剂达芦那韦，GRL-06579 A和GRL-98065对HIV-2和HIV-1蛋白酶的有效性。根据实验数据，抑制剂对HIV-1和HIV-2 PR的亲和力以GRL-06579 A>地瑞那韦> GRL-98065的顺序降低。另一方面，我们的研究结果表明，所有这些抑制剂结合HIV-2比HIV-1蛋白酶，再次与实验结果一致。发现HIV-2相对于HIV-1 PR的结合亲和力降低是由于极性基团（DRV）去溶剂化导致的能量损失增加或抑制剂与PR之间的静电相互作用大小降低所致（GRL-06579 A和GRL-98065）。对于GRL-98065，货车范德华相互作用幅度的降低也有助于结合亲和力的降低。详细了解的分子力的结合和耐药性可能有助于设计有效的抑制剂对HIV-2蛋白酶。
Acquired immune deficiency syndrome (ALDS) 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.