Jayaraman Sudha, Shah Kavita
Bioinformatics Centre, MM, Banaras Hindu University, Varanasi-221 005, India.
In Silico Biol. 2008;8(5-6):427-47.
Bioinformatics tools are employed lately for in silico structure-function analysis of proteins. HIV protease inhibitors nelfinavir and tipranavir belong to the extended multi-ring systems. The intermolecular interactions made by the functional groups of the different residues on the protein molecule are probed with the help of computational tools for protein homology studies so as to identify the functional residues, create single, double, triple mutations using, different bioinformatics servers and to observe the changes brought therein by docking. BLAST, RosettaDesign, PatchDock, Chimera were used in the present study for identifying the inhibitors as better drug targets. The HIV protease-nelfinavir complex (PDB code: 1OHR) and HIV protease V82F/I84V double mutant-tipranavir complex (PDB code: 1D4S) were used as templates for introducing mutations on the HIV protease active site. In this study a structure-based computer-assisted search for the comparison of the two inhibitors of HIV protease was carried out. The results suggest that the two inhibitors nelfinavir and tipranavir could be used for treatment of AIDS by targeting the enzyme HIV protease as neither of the two inhibitors exhibit any cross-reactivity with other human proteins, they readily bind to the mutated enzyme active site and still remain linked with the enzyme-substrate complex in the presence of water molecules. The inhibitor nelfinavir undergoes several changes in hydrogen bonds formation with the introduction of mutations on the HIV protease active site. It either has a positive or a negative inhibitory effect on HIV protease and forms new hydrogen bonds with a shorter bond lengths. Nelfinavir also seems to be an inhibitor of a more narrow specificity as it shows changes in binding bringing thereby conformational changes in the native enzyme. Tipranavir on the other hand seems to be a broad specificity inhibitor as no changes in the bond lengths with the introduction of mutations are observed. Of the two inhibitors tipranavir could be targeted more effectively for designing future drug analogues as it is less vulnerable to mutations. The HIV mutants reported herein could also be used for preliminary identification of specific inhibitors as drugs that may alter the HIV protease activity for medicinal use.
生物信息学工具最近被用于蛋白质的计算机模拟结构-功能分析。HIV蛋白酶抑制剂奈非那韦和替拉那韦属于扩展的多环系统。借助用于蛋白质同源性研究的计算工具，探究蛋白质分子上不同残基的官能团所形成的分子间相互作用，以识别功能残基，使用不同的生物信息学服务器创建单突变、双突变、三突变，并通过对接观察其中的变化。本研究使用BLAST、RosettaDesign、PatchDock、Chimera来确定抑制剂作为更好的药物靶点。HIV蛋白酶-奈非那韦复合物（PDB代码：1OHR）和HIV蛋白酶V82F/I84V双突变体-替拉那韦复合物（PDB代码：1D4S）被用作在HIV蛋白酶活性位点引入突变的模板。本研究基于结构进行了计算机辅助搜索，以比较两种HIV蛋白酶抑制剂。结果表明，两种抑制剂奈非那韦和替拉那韦可通过靶向HIV蛋白酶来治疗艾滋病，因为这两种抑制剂均未与其他人类蛋白质表现出任何交叉反应，它们易于结合到突变的酶活性位点，并且在有水分子存在的情况下仍与酶-底物复合物相连。随着HIV蛋白酶活性位点引入突变，抑制剂奈非那韦在氢键形成方面会发生多种变化。它对HIV蛋白酶要么具有正向抑制作用，要么具有负向抑制作用，并形成键长更短的新氢键。奈非那韦似乎也是一种特异性更窄的抑制剂，因为它显示出结合变化，从而使天然酶发生构象变化。另一方面，替拉那韦似乎是一种特异性较宽的抑制剂，因为引入突变后未观察到键长变化。在这两种抑制剂中，替拉那韦在设计未来药物类似物时可能更有效地作为靶点，因为它对突变的敏感性较低。本文报道的HIV突变体也可用于初步鉴定特定抑制剂，这些抑制剂可作为可能改变HIV蛋白酶活性以供药用的药物。
