Department of Chemistry, Rhodes University, Makhanda 6140, South Africa.
Research Unit in Bioinformatics (RUBi), Rhodes University, Makhanda 6140, South Africa.
Molecules. 2022 Nov 26;27(23):8251. doi: 10.3390/molecules27238251.
It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1-PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro-CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
众所周知，冠状病毒复制过程中的重要酶是 SARS-CoV-2 PLpro 和 SARS-CoV-2 3CLpro，它们都是寻找抗冠状病毒药物的重要靶点。这两种酶负责在 SARS-CoV-2 生命周期中的各种多蛋白位点进行切割。在此，通过计算方法研究了与木瓜蛋白酶样蛋白 PLpro 和主要蛋白酶 3CLpro 复合时，非结构蛋白 Nsp1 和 Nsp2（CS1）之间以及 Nsp2 和 Nsp3（CS2）之间的多蛋白切割序列的动力学。后动力学分析表明，CS1 和 CS2 与 PLpro 复合时都具有更高的稳定性。在这两者中，CS1-PLpro 复合物具有更高的稳定性，而 CS2-PLpro 复合物则观察到 CS2 从 PLpro 活性位点失稳，这表明木瓜蛋白酶样蛋白酶的交换速度更快 CS2 比 CS1。另一方面，3CLpro 主要蛋白酶也显示出 CS1 的稳定性，这表明主蛋白酶也可能在 CS1 点的切割中发挥潜在作用。然而，对于 CLpro-CS2 复合物，在模拟早期就发生了失稳，这表明主蛋白酶与 CS2 的相互作用较差，并且不太可能通过主蛋白酶对多蛋白进行蛋白酶切割。这些发现可以作为开发和设计模拟 CS1 切割位点的有效 COVID-19 抗病毒抑制剂的指南。
