Shekhar Nishant, Sarma Phulen, Prajapat Manisha, Avti Pramod, Kaur Hardeep, Raja Anupam, Singh Harvinder, Bhattacharya Anusuya, Sharma Saurabh, Kumar Subodh, Prakash Ajay, Medhi Bikash
Department of Pharmacology, PGIMER, Chandigarh, India.
Department of Biophysics, PGIMER, Chandigarh, India.
mSystems. 2020 Sep 22;5(5):e00382-20. doi: 10.1128/mSystems.00382-20.
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. The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus's host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的膜锚定刺突（S）蛋白在介导病毒颗粒与宿主细胞受体血管紧张素转换酶2（ACE-2）融合过程中起关键作用。S蛋白S2结构域的融合肽区域为SARS-CoV-2提供了直接与宿主脂质膜融合所需的生物学机制。在本研究中，采用计算机辅助药物设计策略，利用S2结构域的最佳结构来识别美国食品药品监督管理局（FDA）批准的小分子，该结构域具有最佳的相互作用比率、结构特征和能量变量，这些是根据它们在分子对接、分子动力学模拟、分子力学/广义玻恩模型以及分子动力学轨迹的溶剂可及性结合自由能计算中的表现以及统计推断来评估的。在2625种FDA批准的小分子中，琥珀氯霉素、亚胺培南和咪唑脲被证明是在融合肽疏水口袋中结合效果最佳的分子。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赖氨酸790、苏氨酸791、赖氨酸795、天冬氨酸808和谷氨酰胺872残基之间。本研究提供了SARS-CoV-2 S2融合肽区域可行结合残基的结构鉴定，这在病毒的宿主细胞融合和进入机制中至关重要。经典分子力学模拟设定的值模拟了生理标准，以便很好地近似所选药物在生物系统中的动态行为。此处筛选和分析的药物分子具有相关的抗病毒特性，本文对此进行了报道，并且由于它们在本研究中显示出与融合蛋白结合区域结合的特性，可能暗示它们可用于2019冠状病毒病（COVID-19）大流行。
