Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.
Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.
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DOI：
10.1021/ct9004678
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发表时间：
2010-04-13
影响因子：
5.5
通讯作者：
Schiffer, Celia A.
中科院分区：
文献类型：
--
作者：
Cai, Yufeng;Schiffer, Celia A.
达芦那韦（Darunavir，DRV）是一种高亲和力（4.5×10-12 M，ΔG = -15.2 kcal/mol）的HIV-1蛋白酶抑制剂。两种耐药蛋白酶变体FLAP+（L10 I、G48 V、I54 V、V82 A）和ACT（V82 T、I84 V）分别使与DRV的结合亲和力降低1.0 kcal/mol和1.6 kcal/mol。采用MM-PB/GBSA方法和热力学积分法分别计算了DRV与野生型蛋白酶、FLAP+和ACT的绝对和相对结合自由能。自由能分解表明，突变通过扭曲HIV-1蛋白酶的活性位点而赋予抗性，使得失去结合自由能的残基不限于突变位点。具体地，DRV的双-四氢呋喃基氨基甲酸酯部分保持与FLAP+和ACT变体的相互作用，而4 -氨基苯基在FLAP+和ACT复合物中与蛋白酶失去的结合自由能比在野生型蛋白酶中更多，这可以解释结合自由能的大部分损失。这表明4 -氨基苯基的取代可能产生对耐药突变不敏感的新抑制剂。
Darunavir (DRV) is a high affinity (4.5×10-12 M, ΔG = -15.2 kcal/mol) HIV-1 protease inhibitor. Two drug-resistant protease variants FLAP+ (L10I, G48V, I54V, V82A) and ACT (V82T, I84V) decrease the binding affinity with DRV by 1.0 kcal/mol and 1.6 kcal/mol respectively. In this study the absolute and relative binding free energies of DRV with wild-type protease, FLAP+ and ACT were calculated with MM-PB/GBSA and thermodynamic integration methods, respectively. Free energy decomposition elucidated that the mutations conferred resistance by distorting the active site of HIV-1 protease so that the residues that lost binding free energy were not limited to the sites of mutation. Specifically the bis-tetrahydrofuranylurethane moiety of DRV maintained interactions with the FLAP+ and ACT variants, whereas the 4 – amino phenyl group lost more binding free energy with the protease in the FLAP+ and ACT complexes than in the wild-type protease which could account for the majority of the loss in binding free energy. This suggested that replacement of the 4 – amino phenyl group might generate new inhibitors less susceptible to the drug resistant mutations.
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