萨奎纳维尔
达芦那韦
英迪纳维
蛋白酶
洛比那韦
冠状病毒
利托那韦
2019年冠状病毒病(COVID-19)
化学
HIV-1蛋白酶
病毒学
立体化学
人类免疫缺陷病毒(HIV)
生物
酶
生物化学
病毒载量
抗逆转录病毒疗法
医学
疾病
病理
传染病(医学专业)
作者
Xingyu Li,Zhou Fang,Dechang Li,Zhenhai Li
摘要
The pandemic COVID-19 was induced by the novel coronavirus SARS-CoV-2. The virus main protease (Mpro) cleaves the coronavirus polyprotein translated from the viral RNA in the host cells. Because of its crucial role in virus replication, Mpro is a potential drug target for COVID-19 treatment. Herein, we study the interactions between Mpro and three HIV-1 protease (HIV-1 PR) inhibitors, Lopinavir (LPV), Saquinavir (SQV), Ritonavir (RIT), and an inhibitor PF-07321332, by conventional and replica exchange molecular dynamics (MD) simulations. The association/dissociation rates and the affinities of the inhibitors were estimated. The three HIV-1 PR inhibitors exhibit low affinities, while PF-07321332 has the highest affinity among these four simulated inhibitors. Based on cluster analysis, the HIV-1 PR inhibitors bind to Mpro at multiple sites, while PF-07321332 specifically binds to the catalytically activated site of Mpro. The stable and specific binding is because PF-07321332 forms multiple H-bonds to His163 and Glu166 simultaneously. The simulations suggested PF-07321332 could serve as an effective inhibitor with high affinity and shed light on the strategy of drug design and drug repositioning.
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