Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784612914653560832 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8659229 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yuwei computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT wuxiaomin computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT zhaoyizhen computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT chenchun computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT yangzhiwei computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT zhangxiaochun computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT renjiayi computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT wangyueming computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT wuchangwen computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT lichengming computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT chenrongfeng computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT wangxiaoli computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT zhengweihong computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT liaohuaxin computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign AT yuanxiaohui computationalsimulationofhivproteaseinhibitorstothemainproteasemproofsarscov2implicationsforcovid19drugsdesign |