The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues.

中文翻译：

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基于硅结构的 SARS-CoV-2 尖峰糖蛋白 S2 结构域融合肽的批准药物重新定位：分子动力学和结合自由能计算的基本原理。

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的膜锚定刺突 (S) 蛋白在指导宿主细胞受体血管紧张素转换酶 2 (ACE-2) 介导的病毒颗粒融合方面具有关键作用）。S 蛋白 S2 结构域的融合肽区域为 SARS-CoV-2 提供了与宿主脂质膜直接融合所需的生物机制。在我们目前的研究中，计算机辅助药物设计策略被用于使用 S2 域的最佳结构来识别 FDA 批准的小分子，S2 域表现出最佳的相互作用比、结构特征和能量变量，这些是基于它们的评估。分子对接、分子动力学模拟、分子力学/广义 Born 模型和溶剂可及性结合自由能计算分子动力学轨迹，以及统计推断。在 FDA 批准的 2,625 种小分子中，琥珀酸氯霉素、亚胺培南和亚氨脲是在融合肽疏水口袋中结合最好的分子。所选分子的主要相互作用表明融合肽区域的潜在结合位点集中在 Lys790、Thr791、Lys795、Asp808 和 Gln872 残基之间。