Department of Biochemistry, Faculty of Science, Embryonic Stem Cells Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
Centre of Artificial Intelligence in Precision Medicines (CAIPM), King Abdulaziz University, Jeddah, Saudi Arabia.
J Biomol Struct Dyn. 2023 Jul;41(10):4744-4755. doi: 10.1080/07391102.2022.2072392. Epub 2022 May 5.
The coronavirus disease (COVID-19) pandemic has rapidly extended globally and killed approximately 5.83 million people all over the world. But, to date, no effective therapeutic against the disease has been developed. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enters the host cell through the spike glycoprotein (S protein) of the virus. Subsequently, RNA-dependent RNA polymerase (RdRp) and main protease (M) of the virus mediate viral transcription and replication. Mechanistically inhibition of these proteins can hinder the transcription as well as replication of the virus. Recently oxysterols and its derivative, such as 25 (S)-hydroxycholesterol (25-HC) has shown antiviral activity against SARS-CoV-2. But the exact mechanisms and their impact on RdRp and M have not been explored yet. Therefore, the study aimed to identify the inhibitory activity of 25-HC against the viral enzymes RdRp and M simultaneously. Initially, a molecular docking simulation was carried out to evaluate the binding activity of the compound against the two proteins. The pharmacokinetics (PK) and toxicity parameters were analyzed to observe the 'drug-likeness' properties of the compound. Additionally, molecular dynamics (MD) simulation was performed to confirm the binding stability of the compound to the targeted protein. Furthermore, molecular mechanics generalized Born surface area (MM-GBSA) was used to predict the binding free energies of the compound to the targeted protein. Molecular docking simulation identified low glide energy -51.0 kcal/mol and -35.0 kcal/mol score against the RdRp and M respectively, where MD simulation found good binding stability of the compound to the targeted proteins. In addition, the MM/GBSA approach identified a good value of binding free energies (ΔG bind) of the compound to the targeted proteins. Therefore, the study concludes that the compound 25-HC could be developed as a treatment and/or prevention option for SARS-CoV-2 disease-related complications. Although, experimental validation is suggested for further evaluation of the work.Communicated by Ramaswamy H. Sarma.
新型冠状病毒（COVID-19）疫情在全球迅速蔓延，导致全球约 583 万人死亡。但是，迄今为止，尚未开发出针对该疾病的有效治疗方法。该疾病是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的，病毒通过刺突糖蛋白（S 蛋白）进入宿主细胞。随后，病毒的 RNA 依赖性 RNA 聚合酶（RdRp）和主要蛋白酶（M）介导病毒的转录和复制。从机制上讲，抑制这些蛋白可以阻碍病毒的转录和复制。最近，胆甾醇及其衍生物，如 25-羟基胆固醇（25-HC），已显示出对 SARS-CoV-2 的抗病毒活性。但是，确切的机制及其对 RdRp 和 M 的影响尚未得到探索。因此，本研究旨在同时鉴定 25-HC 对病毒酶 RdRp 和 M 的抑制活性。最初，进行了分子对接模拟以评估该化合物对两种蛋白质的结合活性。分析了药代动力学（PK）和毒性参数，以观察化合物的“类药性”特性。此外，进行了分子动力学（MD）模拟，以确认化合物与靶蛋白的结合稳定性。此外，使用分子力学广义 Born 表面积（MM-GBSA）预测了化合物与靶蛋白的结合自由能。分子对接模拟确定了针对 RdRp 和 M 的低滑行能-51.0 kcal/mol 和-35.0 kcal/mol 评分，其中 MD 模拟发现化合物与靶蛋白具有良好的结合稳定性。此外，MM/GBSA 方法确定了化合物与靶蛋白的结合自由能（ΔG bind）的良好值。因此，该研究得出结论，化合物 25-HC 可被开发为治疗和/或预防 SARS-CoV-2 疾病相关并发症的方法。尽管建议进行实验验证以进一步评估该工作。由 Ramaswamy H. Sarma 传达。
