Tautomerism and magnesium chelation of HIV-1 integrase inhibitors: a theoretical study.
Tautomerism and magnesium chelation of HIV-1 integrase inhibitors: a theoretical study.
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HIV-1 整合酶抑制剂的互变异构和镁螯合：理论研究。
DOI：
10.1002/cmdc.201000039
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发表时间：
2010
期刊：
影响因子：
3.4
通讯作者：
Nicklaus,MarcC
中科院分区：
文献类型：
--
作者：
Liao,Chenzhong;Nicklaus,MarcC
在B3 LYP/6 - 311++G（d，p）水平上，研究了4种HIV-1整合酶（IN）抑制剂原型化合物α，γ-二酮酸、α，γ-二酮三唑、二羟基嘧啶酰胺和4-喹诺酮-3-羧酸的互变异构和过渡态.为了研究这些互变异构体与两个镁离子的可能的螯合模式-一个重要的抑制过程-我们模拟了三个甲酸，四个水分子和两个Mg 2+离子作为模板模仿IN的结合位点的组装。DFT计算结果表明，去质子化的烯醇化或酚羟基的特定互变异构体在水中导致最稳定的复合物，与两个镁离子分开的距离约为3.70至3.74 <$，和每个镁离子在八面体的中心。 基于4-喹诺酮-3-羧酸骨架的候选药物GS-9137（吉利德）及其类似物形成相似但不同的螯合模式。当复合物中的一个水分子被模拟病毒DNA末端3′-OH的甲醇分子取代时，保留了良好的螯合复合物。这支持了以下假设：在IN的结合位点，病毒DNA的末端3′-OH通过螯合作用与一个Mg 2+相互作用。
The tautomerism and corresponding transition states of four authentic HIV‐1 integrase (IN) inhibitor prototype structures, α,γ‐diketo acid, α,γ‐diketotriazole, dihydroxypyrimidine carboxamide and 4‐quinolone‐3‐carboxylic acid, were investigated at the B3LYP/6‐311++G(d,p) level in vacuum and in aqueous solvent models. To study the possible chelating modes of these tautomers with two magnesium ions—a process important for inhibition—we modeled an assembly of three formic acids, four water molecules and two Mg2+ions as a template mimicking the binding site of IN. The DFT calculation results show that deprotonated enolized or phenolic hydroxy groups of specific tautomers in water lead to the most stable complexes, with the two magnesium ions separated by a distance of approximately 3.70 to 3.74 Å, and with each magnesium ion at the center of an octahedron. The drug candidate GS‐9137 (Gilead), based on the 4‐quinolone‐3‐carboxylic acid scaffold, and its analogues form similar but different chelating modes. When one water molecule in the complex is replaced by a methanol molecule, which mimics the terminal 3′‐OH of viral DNA, a good chelating complex is retained. This supports the hypothesis that, in the binding site of IN after 3′‐processing, the terminal 3′‐OH of viral DNA interacts with one Mg2+by chelation.