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Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors

Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking...

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Autores principales: Zong, Keli, Xu, Lei, Hou, Yuxin, Zhang, Qian, Che, Jinjing, Zhao, Lei, Li, Xingzhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623395/
https://www.ncbi.nlm.nih.gov/pubmed/34834044
http://dx.doi.org/10.3390/molecules26226944
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author Zong, Keli
Xu, Lei
Hou, Yuxin
Zhang, Qian
Che, Jinjing
Zhao, Lei
Li, Xingzhou
author_facet Zong, Keli
Xu, Lei
Hou, Yuxin
Zhang, Qian
Che, Jinjing
Zhao, Lei
Li, Xingzhou
author_sort Zong, Keli
collection PubMed
description Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5–55.43 μM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081–1.53 μM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors.
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spelling pubmed-86233952021-11-27 Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors Zong, Keli Xu, Lei Hou, Yuxin Zhang, Qian Che, Jinjing Zhao, Lei Li, Xingzhou Molecules Article Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5–55.43 μM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081–1.53 μM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors. MDPI 2021-11-17 /pmc/articles/PMC8623395/ /pubmed/34834044 http://dx.doi.org/10.3390/molecules26226944 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
Zong, Keli
Xu, Lei
Hou, Yuxin
Zhang, Qian
Che, Jinjing
Zhao, Lei
Li, Xingzhou
Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title_full Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title_fullStr Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title_full_unstemmed Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title_short Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
title_sort virtual screening and molecular dynamics simulation study of influenza polymerase pb2 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623395/
https://www.ncbi.nlm.nih.gov/pubmed/34834044
http://dx.doi.org/10.3390/molecules26226944
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