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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >In silico design of novel broad anti-HIV-1 agents based on glycosphingolipid beta-galactosylceramide, a high-affinity receptor for the envelope gp120 V3 loop
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In silico design of novel broad anti-HIV-1 agents based on glycosphingolipid beta-galactosylceramide, a high-affinity receptor for the envelope gp120 V3 loop

机译：在计算机上设计基于糖鞘脂β-半乳糖基神经酰胺的新型广泛抗HIV-1药物，这是信封gp120 V3环的高亲和力受体

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摘要

Novel anti-Human immunodeficiency virus (HIV)-1 agents targeting the V3 loop of envelope protein gp120 were designed by computer modeling based on glycosphingolipid beta-galactosylceramide (beta-GalCer), which is an alternative receptor allowing HIV-1 entry into CD4-negative cells of neural and colonic origin. Models of these beta-GalCer analogs bound to the V3 loops from five various HIV-1 variants were generated by molecular docking and their stability was estimated by molecular dynamics (MDs) and binding free energy simulations. Specific binding to the V3 loop was accomplished primarily by non-conventional XH horizontal ellipsis pi interactions between CH/OH sugar groups of the glycolipids and the conserved V3 residues with pi-conjugated side chains. The designed compounds were found to block the tip and/or the base of the V3 loop, which form invariant structural motifs that contain residues critical for cell tropism. With the MDs calculations, the docked models of the complexes of the beta-GalCer analogs with V3 are energetically stable in all of the cases of interest and exhibit low values of free energy of their formation. Based on the data obtained, these compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.
机译：通过基于糖鞘脂β-半乳糖基神经酰胺（β-GalCer）的计算机建模，设计了针对包膜蛋白gp120的V3环的新型抗人类免疫缺陷病毒（HIV）-1药物，该药物是允许HIV-1进入CD4的另一种受体。神经和结肠起源的阴性细胞。这些β-GalCer类似物的模型是通过分子对接生成的，它们与来自五个不同HIV-1变体的V3环结合，并通过分子动力学（MD）和结合自由能模拟来评估其稳定性。与V3环的特异性结合主要是通过糖脂的CH / OH糖基与带有pi共轭侧链的保守V3残基之间的非常规XH水平省略号pi相互作用实现的。发现设计的化合物可阻断V3环的末端和/或碱基，从而形成不变的结构基序，其中包含对细胞向性至关重要的残基。通过MD计算，β-GalCer类似物与V3的复合物的对接模型在所有感兴趣的情况下在能量上都是稳定的，并且其形成的自由能值较低。根据获得的数据，这些化合物被认为是合理设计新颖，有效和广谱抗HIV-1治疗剂的有前途的基本结构。

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