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首页> 外文期刊>Bioorganic and medicinal chemistry >Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations.
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Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations.

机译：作为潜在的HIV-1 PR抑制剂的新型富勒烯类似物的计算设计：使用3D QSAR，分子对接和分子动力学模拟分析富勒烯抑制剂与HIV-1 PR残基之间的结合相互作用。

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A series of experimentally reported as well as computationally designed monoadducts and bisadducts of [60]fullerene analogues have been used in order to analyze the binding interactions between fullerene based inhibitors and HIV-1 PR employing docking studies. MD simulations of ligand-free and the inhibitor bound HIV-1 PR systems complemented the above studies and provided proper input structure of HIV-1 PR in docking simulations. The obtained results revealed a different orientation of the beta-hairpin flaps at these two systems. In inhibitor bound system, the flaps of the enzyme are pulled in toward the bottom of the active site (the closed form) while, in ligand-free system flaps shifted away from the dual Asp25 catalytic site and this system adopts a semi-open form. The structural analysis of these systems at catalytic and flexible flap regions of the HIV-1 PR through the simulation, assisted in understanding the structural preferences of these regions, as well as, the adopted orientations of fullerene derivatives within the active site of the enzyme. Five different combinations of steroelectronic fields of 3D QSAR/CoMSIA models were obtained from the set of biologically evaluated and computationally designed fullerene derivatives (training set=43, test set=6) in order to predict novel compounds with improved inhibition effect. The best 3D QSAR/CoMSIA model yielded a cross validated r(2) value of 0.739 and a non-cross validated r(2) value of 0.993. The derived model indicated the importance of steric (42.6%), electrostatic (12.7%), H-bond donor (16.7%) and H-bond acceptor (28.0%) contributions. The derived contour plots together with de novo drug design were then used as pilot models for proposing the novel analogues with enhanced binding affinities. Such structures may trigger the interest of medicinal chemists for novel HIV-1 PR inhibitors possessing higher bioactivity.
机译：为了研究基于富勒烯的抑制剂与HIV-1 PR之间的结合相互作用，已使用对接研究方法，使用了一系列实验报告和计算设计的[60]富勒烯类似物单加合物和双加合物。不含配体和结合抑制剂的HIV-1 PR系统的MD模拟对上述研究进行了补充，并在对接模拟中提供了HIV-1 PR的适当输入结构。获得的结果揭示了在这两个系统中β-发夹襟翼的取向不同。在抑制剂结合系统中，酶的瓣向着活性位点的底部（封闭形式）被拉入，而在无配体的系统中，酶的瓣从双Asp25催化位点移开，并且该系统采用半开放形式。通过模拟对HIV-1 PR催化和柔性瓣区域的这些系统进行结构分析，有助于了解这些区域的结构偏好，以及在酶活性位点内富勒烯衍生物的采用方向。从一组经过生物学评估和计算设计的富勒烯衍生物（训练集= 43，测试集= 6）中获得了3D QSAR / CoMSIA模型的五种不同立体电子场组合，以预测具有改善抑制作用的新型化合物。最好的3D QSAR / CoMSIA模型产生的交叉验证的r（2）值为0.739，非交叉验证的r（2）值为0.993。推导的模型表明了位阻（42.6％），静电（12.7％），氢键供体（16.7％）和氢键受体（28.0％）的重要性。然后将导出的轮廓图与从头药物设计一起用作试验模型，以提出具有增强结合亲和力的新型类似物。这样的结构可能引起医学化学家对具有更高生物活性的新型HIV-1 PR抑制剂的兴趣。

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