Karki Rajeshri G, Tang Yun, Burke Terrence R, Nicklaus Marc C
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA.
J Comput Aided Mol Des. 2004 Dec;18(12):739-60. doi: 10.1007/s10822-005-0365-5. Epub 2005 Jun 27.
We report structural models of the full-length integrase enzyme (IN) of the human immunodeficiency virus type 1 (HIV-1) and its complex with viral and human DNA. These were developed by means of molecular modeling techniques using all available experimental evidence, including X-ray crystallographic and NMR structures of portions of the full-length protein. Special emphasis was placed on obtaining a model of the enzyme's active site with the viral DNA apposed to it, based on the hypothesis that such a model would allow structure-based design of inhibitors that retain activity in vivo. This was because bound DNA might be present in vivo after 3'-processing but before strand transfer. These structural models were used to study the potential binding modes of various diketo-acid HIV-1 IN inhibitors (many of them preferentially inhibiting strand transfer) for which no experimentally derived complexed structures are available. The results indicate that the diketo-acid IN inhibitors probably chelate the metal ion in the catalytic site and also prevent the exposure of the 3'-processed end of the viral DNA to human DNA.
我们报道了1型人类免疫缺陷病毒（HIV-1）全长整合酶（IN）及其与病毒和人类DNA复合物的结构模型。这些模型是通过分子建模技术，利用所有可用的实验证据构建的，包括全长蛋白部分的X射线晶体学和核磁共振结构。特别强调基于这样一种假设来获得酶活性位点与病毒DNA毗邻的模型，即这种模型将有助于基于结构设计在体内保持活性的抑制剂。这是因为结合的DNA可能在3'加工后但在链转移前存在于体内。这些结构模型被用于研究各种二酮酸HIV-1整合酶抑制剂（其中许多优先抑制链转移）的潜在结合模式，对于这些抑制剂尚无实验得出的复合结构。结果表明，二酮酸整合酶抑制剂可能螯合催化位点的金属离子，并防止病毒DNA的3'加工末端暴露于人类DNA。
