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:	Keli Zong, Lei Xu, Yuxin Hou, Qian Zhang, Jinjing Che, Lei Zhao, Xingzhou Li
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	virtual screening influenza virus polymerase basic protein 2 inhibitor molecular dynamics simulations Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/69117a614db3484cbfd8d337b0ade3c6
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spelling	oai:doaj.org-article:69117a614db3484cbfd8d337b0ade3c62021-11-25T18:28:41ZVirtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors10.3390/molecules262269441420-3049https://doaj.org/article/69117a614db3484cbfd8d337b0ade3c62021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/6944https://doaj.org/toc/1420-3049Influenza 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.Keli ZongLei XuYuxin HouQian ZhangJinjing CheLei ZhaoXingzhou LiMDPI AGarticlevirtual screeninginfluenza viruspolymerase basic protein 2inhibitormolecular dynamics simulationsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6944, p 6944 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	virtual screening influenza virus polymerase basic protein 2 inhibitor molecular dynamics simulations Organic chemistry QD241-441
spellingShingle	virtual screening influenza virus polymerase basic protein 2 inhibitor molecular dynamics simulations Organic chemistry QD241-441 Keli Zong Lei Xu Yuxin Hou Qian Zhang Jinjing Che Lei Zhao Xingzhou Li Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
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.
format	article
author	Keli Zong Lei Xu Yuxin Hou Qian Zhang Jinjing Che Lei Zhao Xingzhou Li
author_facet	Keli Zong Lei Xu Yuxin Hou Qian Zhang Jinjing Che Lei Zhao Xingzhou Li
author_sort	Keli Zong
title	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_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_sort	virtual screening and molecular dynamics simulation study of influenza polymerase pb2 inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/69117a614db3484cbfd8d337b0ade3c6
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Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors

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