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Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design

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 replica...

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Autores principales: Yu, Wei, Wu, Xiaomin, Zhao, Yizhen, Chen, Chun, Yang, Zhiwei, Zhang, Xiaochun, Ren, Jiayi, Wang, Yueming, Wu, Changwen, Li, Chengming, Chen, Rongfeng, Wang, Xiaoli, Zheng, Weihong, Liao, Huaxin, Yuan, Xiaohui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659229/
https://www.ncbi.nlm.nih.gov/pubmed/34885967
http://dx.doi.org/10.3390/molecules26237385
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author Yu, Wei
Wu, Xiaomin
Zhao, Yizhen
Chen, Chun
Yang, Zhiwei
Zhang, Xiaochun
Ren, Jiayi
Wang, Yueming
Wu, Changwen
Li, Chengming
Chen, Rongfeng
Wang, Xiaoli
Zheng, Weihong
Liao, Huaxin
Yuan, Xiaohui
author_facet Yu, Wei
Wu, Xiaomin
Zhao, Yizhen
Chen, Chun
Yang, Zhiwei
Zhang, Xiaochun
Ren, Jiayi
Wang, Yueming
Wu, Changwen
Li, Chengming
Chen, Rongfeng
Wang, Xiaoli
Zheng, Weihong
Liao, Huaxin
Yuan, Xiaohui
author_sort Yu, Wei
collection PubMed
description 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.
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spelling pubmed-86592292021-12-10 Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design Yu, Wei Wu, Xiaomin Zhao, Yizhen Chen, Chun Yang, Zhiwei Zhang, Xiaochun Ren, Jiayi Wang, Yueming Wu, Changwen Li, Chengming Chen, Rongfeng Wang, Xiaoli Zheng, Weihong Liao, Huaxin Yuan, Xiaohui Molecules Article 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. MDPI 2021-12-05 /pmc/articles/PMC8659229/ /pubmed/34885967 http://dx.doi.org/10.3390/molecules26237385 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yu, Wei
Wu, Xiaomin
Zhao, Yizhen
Chen, Chun
Yang, Zhiwei
Zhang, Xiaochun
Ren, Jiayi
Wang, Yueming
Wu, Changwen
Li, Chengming
Chen, Rongfeng
Wang, Xiaoli
Zheng, Weihong
Liao, Huaxin
Yuan, Xiaohui
Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title_full Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title_fullStr Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title_full_unstemmed Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title_short Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design
title_sort computational simulation of hiv protease inhibitors to the main protease (mpro) of sars-cov-2: implications for covid-19 drugs design
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659229/
https://www.ncbi.nlm.nih.gov/pubmed/34885967
http://dx.doi.org/10.3390/molecules26237385
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