Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir.
Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir.
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DOI：
10.1038/s41598-020-77700-z
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发表时间：
2020-12-01
影响因子：
4.6
通讯作者：
Moro S
中科院分区：
文献类型：
--
作者：
Bolcato G;Bissaro M;Pavan M;Sturlese M;Moro S
冠状病毒 SARS-CoV-2 是最近发现的一种单链 RNA β 冠状病毒，可导致一种被称为 2019 年冠状病毒病的严重呼吸道疾病，该疾病正在迅速传播。为了应对缺乏有效治疗策略的问题，中国卫生当局开始研究洛匹那韦和利托那韦的使用，这两种药物此前曾针对艾滋病毒/艾滋病病毒感染的治疗和预防进行了优化。尽管这两种药物已在临床使用，但仍不清楚它们在分子水平上对 SARS-CoV-2 可能的作用机制的信息。最近，SARS-CoV-2 主要蛋白酶 (Mpro)（也称为 C30 内肽酶）的晶体结构发表。从这一重要的结构信息开始，在目前的工作中，我们利用了监督分子动力学，这是一种新兴的计算技术，可以在原子水平上研究配体从未结合态到最终结合态的识别过程。在这项研究中，我们提供了对洛匹那韦、利托那韦和奈非那韦这三种潜在 C30 肽链内切酶抑制剂的整个识别途径的分子见解，最后一种由于对结构相关的 SARS-CoV 蛋白酶表现出有前景的体外活性而被考虑在内。
Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019, which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited supervised molecular dynamics, an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole recognition pathway of Lopinavir, Ritonavir, and Nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease.