Department of Medical Laboratory Sciences, College of Applied Medical Sciences in Al-Quwayiyah, Shaqra University, Saudi Arabia.
Department of Pathology, Clinical Biochemistry Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Comb Chem High Throughput Screen. 2023;26(6):1196-1203. doi: 10.2174/1386207325666220816141028.
SARS-CoV-2 emerged in late 2019 and caused COVID-19. Patients treated with Zyesami were found to have a 3-fold decrease in respiratory failure and improved clinical outcomes. It was reported that Zyesami inhibits RNA replication of SARS-CoV-2, including several non-structural proteins essential in viral RNA replication. SARS-CoV-2 is a distinctive virus that requires nsp10 and nsp16 for its methyltransferases activity which is crucial for RNA stability and protein synthesis.
We aimed the in silico determination of inhibitory consequences of Zyesami on the SARS-CoV-2 nsp10/nsp16 complex. Targeting SARS-CoV-2 nsp10/ nsp16 protein complex may be used to develop a drug against COVID-19.
I-TASSER was used for secondary structure prediction of Zyesami. CABS-dock was used to model Zyesami with SARS-CoV-2 nsp16 interaction. The docked complex was visualized using PyMol. The quality of the docking model was checked by using ProQdock.
The 3D structure of SARS-CoV 2, nsp10/nsp16 showed that essential interactions exist between nsp10 and nsp16. Significant contact areas of Zyesami exist across amino acid residues of nsp10; Asn-Thr, Val57-Pro, Gly-Ser, Cys-Pro, Lys-Tyr. In addition, polar contacts between nsp16 and Zyesami are Asn-Ser, Val-Asn, Gly-Tyr, Gln-Lys, Asn- Arg, Ser-Arg, Ser-Arg, Lys-Arg, Asr-Thr, Lys-Asp, Lys-Asp, and Gln-Asp the residues are shown of nsp16 and Zyesami respectively.
The structural bioinformatics analyses have indicated the potential binding specificity of Zyesami and nsp16. Data predict how the initial binding of Zyesami with nsp10 and nsp16 may occur. Moreover, this binding could significantly inhibit the 2 -O-MTase activity of the SARSCoV nsp10/16 complex.
SARS-CoV-2 于 2019 年底出现，并引发了 COVID-19。研究发现，接受 Zyesami 治疗的患者呼吸衰竭的发生率降低了 3 倍，临床结局得到改善。有报道称，Zyesami 抑制了 SARS-CoV-2 的 RNA 复制，包括病毒 RNA 复制中几种必不可少的非结构蛋白。SARS-CoV-2 是一种独特的病毒，需要 nsp10 和 nsp16 来发挥其甲基转移酶活性，这对于 RNA 稳定性和蛋白质合成至关重要。
我们旨在通过计算机模拟确定 Zyesami 对 SARS-CoV-2 nsp10/nsp16 复合物的抑制作用。针对 SARS-CoV-2 nsp10/nsp16 蛋白复合物可能是开发 COVID-19 药物的一种方法。
使用 I-TASSER 进行 Zyesami 的二级结构预测。使用 CABS-dock 对 Zyesami 与 SARS-CoV-2 nsp16 的相互作用进行建模。使用 PyMol 可视化对接复合物。使用 ProQdock 检查对接模型的质量。
SARS-CoV-2、nsp10/nsp16 的 3D 结构表明，nsp10 和 nsp16 之间存在重要的相互作用。Zyesami 与 nsp10 氨基酸残基之间存在显著的接触区域，包括 Asn-Thr、Val57-Pro、Gly-Ser、Cys-Pro 和 Lys-Tyr。此外，nsp16 和 Zyesami 之间的极性接触包括 nsp16 的 Asn-Ser、Val-Asn、Gly-Tyr、Gln-Lys、Asn-Arg、Ser-Arg、Ser-Arg、Lys-Arg、Asr-Thr、Lys-Asp、Lys-Asp 和 Gln-Asp，而 Zyesami 的相应残基分别为 Lys-Asp、Lys-Asp 和 Gln-Asp。
结构生物信息学分析表明了 Zyesami 与 nsp16 的潜在结合特异性。数据预测了 Zyesami 与 nsp10 和 nsp16 的初始结合方式。此外，这种结合可能会显著抑制 SARS-CoV nsp10/16 复合物的 2-O-MTase 活性。
