Abstract
SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM–GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.
Highlights
Coronavirus Disease 2019 (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) infection is spreading globally and has posed a significant threat to the human health and economic stability over the world [1,2]
The ma process of the virus is highly dependent on main protease (Mpro), in which it can clea2 vofe17the pol body produced by the transcription of viral genomic RNA in host cells to prod proteins required for virus replication, such as RNA-dependent RNA polymerase
This study used molecular docking calculations, molecular dynamics (MD) simulations, mechanics–generalized Born surface area (MM–GBSA), and pharmacophore analysis to carefully study the interaction of these small molecules with SARS-CoV-2 Mpro
Summary
Coronavirus Disease 2019 (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) infection is spreading globally and has posed a significant threat to the human health and economic stability over the world [1,2]. SARS-CoV-2 and SARS-CoV have a very high homology, with the ability of spreading from person to person through respiratory droplet transmission and contact transmission After infection, they can attack vascular endothelial cells, epithelial cells, and immune cells, resulting in severe acute respiratory syndrome. Based on data from the World Health Organization, at least 24 novel vaccines and at least two protomers, and each protomer is composed of three domains (I, II, and III), a in Figure 1 (PDB: 6LU7). It has atypical Cys-His doublets (His and Cys145) in between domain I and II, which are two catalytical sites of Mpro [5,6]. The ma process of the virus is highly dependent on Mpro, in which it can clea vofe17the pol body produced by the transcription of viral genomic RNA in host cells to prod proteins required for virus replication, such as RNA-dependent RNA polymerase
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