Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Front Immunol. 2023 Feb 8;14:1113321. doi: 10.3389/fimmu.2023.1113321. eCollection 2023.
With the immensely growing outbreaks of hantavirus with still no effective treatment available, there is an urgent need of exploring new computational approaches which will target potential virulent proteins that will eventually reduce its growth. In this study, an envelope glycoprotein, Gn, was targeted. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry receptor-mediated endocytosis and endosomal membrane fusion. Inhibitors are herein proposed to negate its action mechanism. On the basis of the scaffolds of favipiravir, a FDA compound already used against hantavirus, a library was designed using a 2D fingerprinting approach. Upon molecular docking analysis, the top four docked compounds-(1) favipiravir (-4.5 kcal/mol), (2) N-hydroxy-3-oxo-3, 4-dihydropyrazine-2-carboxamide (-4.7 kcal/mol), (3) N, 5, 6-trimethyl-2-oxo-1H-pyrazine-3-carboxamide (-4.5 kcal/mol), and (4) 3-propyl-1H-pyrazin-2-one (-3.8)-were prioritized on the basis of the lowest binding energies score. Through molecular docking, the best-categorized compound was subjected to molecular dynamics simulation for a 100-ns time span. Molecular dynamics sheds light on each ligand behavior within the active site. Among the four complexes, only favipiravir and 6320122 compound were found to be stable inside the pocket. This is due to the presence of common rings, pyrazine and carboxamide ring, which make a significant interaction with active key residues Furthermore, the MMPB/GBSA binding free energy analysis calculated for all complexes supported the dynamics results by calculating the most stable values for favipiravir complex (-9.9933 and -8.6951 kcal/mol) and for 6320122 compound complex (-13.8675 and -9.3439 kcal/mol), which demonstrated that the selected compounds have a proper binding affinity with the targeted proteins. The hydrogen bond analysis similarly revealed a strong bonding interaction. The results yielded a strong interaction between the enzyme and the inhibitor throughout the simulation; thus, the inhibitor has the potential to become a lead compound and could be subjected to experimental evaluation to unveil their blockage ability.
由于汉坦病毒的爆发呈指数级增长，但目前尚无有效的治疗方法，因此迫切需要探索新的计算方法，以针对潜在的毒力蛋白，最终抑制其生长。在这项研究中，我们选择了包膜糖蛋白 Gn 作为研究对象。糖蛋白是中和抗体的唯一靶点，它驱动病毒进入细胞、受体介导的内吞作用和内体膜融合。本文提出了抑制剂来中和其作用机制。以法匹拉韦（一种已被 FDA 批准用于抗汉坦病毒的化合物）为骨架，我们采用二维指纹图谱方法设计了一个化合物库。通过分子对接分析，排名前四的对接化合物分别是：（1）法匹拉韦（-4.5 kcal/mol）、（2）N-羟基-3-氧代-3,4-二氢吡嗪-2-甲酰胺（-4.7 kcal/mol）、（3）N,5,6-三甲基-2-氧代-1H-吡嗪-3-甲酰胺（-4.5 kcal/mol）和（4）3-丙基-1H-吡嗪-2-酮（-3.8）。这是基于最低结合能得分对化合物进行了优先级排序。通过分子对接，我们对最佳分类化合物进行了 100 纳秒的分子动力学模拟。分子动力学模拟揭示了每个配体在活性位点内的行为。在这四个复合物中，只有法匹拉韦和 6320122 化合物被发现稳定在口袋内。这是由于存在共同的环，即吡嗪环和甲酰胺环，它们与活性关键残基发生了显著相互作用。此外，所有复合物的 MMPB/GBSA 结合自由能分析通过计算法匹拉韦复合物（-9.9933 和-8.6951 kcal/mol）和 6320122 化合物复合物（-13.8675 和-9.3439 kcal/mol）的最稳定值，为动力学结果提供了支持，这表明所选化合物与靶蛋白具有适当的结合亲和力。氢键分析同样揭示了强烈的键合相互作用。结果表明，在整个模拟过程中，酶与抑制剂之间存在强烈的相互作用；因此，抑制剂有可能成为一种先导化合物，并可进行实验评估以揭示其阻断能力。
