Cargando…
Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation
Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune response...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899470/ https://www.ncbi.nlm.nih.gov/pubmed/35264955 http://dx.doi.org/10.3389/fphar.2022.817715 |
_version_ | 1784663923713114112 |
---|---|
author | Tian, Xiaoyan Zhao, Quanfeng Chen, Xiaohong Peng, Zhe Tan, Xiaodan Wang, Qin Chen, Lin Yang, Yang |
author_facet | Tian, Xiaoyan Zhao, Quanfeng Chen, Xiaohong Peng, Zhe Tan, Xiaodan Wang, Qin Chen, Lin Yang, Yang |
author_sort | Tian, Xiaoyan |
collection | PubMed |
description | Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19. Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking. Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC(50) values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site. Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19. |
format | Online Article Text |
id | pubmed-8899470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88994702022-03-08 Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation Tian, Xiaoyan Zhao, Quanfeng Chen, Xiaohong Peng, Zhe Tan, Xiaodan Wang, Qin Chen, Lin Yang, Yang Front Pharmacol Pharmacology Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19. Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking. Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC(50) values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site. Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19. Frontiers Media S.A. 2022-02-21 /pmc/articles/PMC8899470/ /pubmed/35264955 http://dx.doi.org/10.3389/fphar.2022.817715 Text en Copyright © 2022 Tian, Zhao, Chen, Peng, Tan, Wang, Chen and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Tian, Xiaoyan Zhao, Quanfeng Chen, Xiaohong Peng, Zhe Tan, Xiaodan Wang, Qin Chen, Lin Yang, Yang Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title | Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title_full | Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title_fullStr | Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title_full_unstemmed | Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title_short | Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation |
title_sort | discovery of novel and highly potent inhibitors of sars cov-2 papain-like protease through structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics simulations, and biological evaluation |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899470/ https://www.ncbi.nlm.nih.gov/pubmed/35264955 http://dx.doi.org/10.3389/fphar.2022.817715 |
work_keys_str_mv | AT tianxiaoyan discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT zhaoquanfeng discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT chenxiaohong discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT pengzhe discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT tanxiaodan discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT wangqin discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT chenlin discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation AT yangyang discoveryofnovelandhighlypotentinhibitorsofsarscov2papainlikeproteasethroughstructurebasedpharmacophoremodelingvirtualscreeningmoleculardockingmoleculardynamicssimulationsandbiologicalevaluation |