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首页> 美国卫生研究院文献>Molecules >Integrated Computational Tools for Identification of CCR5 Antagonists as Potential HIV-1 Entry Inhibitors: Homology Modeling Virtual Screening Molecular Dynamics Simulations and 3D QSAR Analysis
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Integrated Computational Tools for Identification of CCR5 Antagonists as Potential HIV-1 Entry Inhibitors: Homology Modeling Virtual Screening Molecular Dynamics Simulations and 3D QSAR Analysis

机译：用于识别CCR5拮抗剂作为潜在HIV-1进入抑制剂的集成计算工具：同源性建模虚拟筛选分子动力学模拟和3D QSAR分析

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摘要

Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated rcv2 value of 0.84 using three principal components and non-cross-validated r2 value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery.
机译：利用集成的计算机计算技术，包括同源性建模，基于结构和基于药效团的虚拟筛选，分子动力学模拟，残基能量分解分析和基于原子的3D-QSAR分析，我们提出了十种新型化合物作为潜在的CCR5-依赖的HIV-1进入抑制剂。通过验证的对接计算，结合自由能显示，与FDA批准的HIV-1进入抑制剂maraviroc相比，新颖的导线显示出与CCR5更好的结合亲和力，并且在临床上使用。对平均MD结构的每个残基相互作用能分解分析表明，疏水活性残基Trp86，Tyr89和Tyr108对抑制剂结合的贡献最大。经过验证的3D-QSAR模型使用三个主成分显示出较高的交叉验证的rcv 2 值为0.84，未交叉验证的r 2 值为0.941。还发现测试集中和训练集中的几乎所有化合物都产生了良好的预测值。从这项研究中获得的信息可以阐明一系列新的潜在潜在艾滋病毒进入抑制剂中的先导化合物的活性，并可以作为药物设计和开发机制中的有力工具。

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