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Article

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

1
Chemical Engineering and Environmental Engineering, College of Chemistry, Liaoning Shihua University, Fushun 113001, China
2
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
3
Tianjin Children Hospital, Tianjin Medical University, Tianjing 300074, China
4
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2021, 26(22), 6944; https://doi.org/10.3390/molecules26226944
Submission received: 26 September 2021 / Revised: 10 November 2021 / Accepted: 12 November 2021 / Published: 17 November 2021

Abstract

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.
Keywords: virtual screening; influenza virus; polymerase basic protein 2; inhibitor; molecular dynamics simulations virtual screening; influenza virus; polymerase basic protein 2; inhibitor; molecular dynamics simulations

Correction Statement

This article has been republished with a minor correction to some authors' affiliations. This change does not affect the scientific content of the article.

Share and Cite

MDPI and ACS Style

Zong, K.; Xu, L.; Hou, Y.; Zhang, Q.; Che, J.; Zhao, L.; Li, X. Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors. Molecules 2021, 26, 6944. https://doi.org/10.3390/molecules26226944

AMA Style

Zong K, Xu L, Hou Y, Zhang Q, Che J, Zhao L, Li X. Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors. Molecules. 2021; 26(22):6944. https://doi.org/10.3390/molecules26226944

Chicago/Turabian Style

Zong, Keli, Lei Xu, Yuxin Hou, Qian Zhang, Jinjing Che, Lei Zhao, and Xingzhou Li. 2021. "Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors" Molecules 26, no. 22: 6944. https://doi.org/10.3390/molecules26226944

APA Style

Zong, K., Xu, L., Hou, Y., Zhang, Q., Che, J., Zhao, L., & Li, X. (2021). Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors. Molecules, 26(22), 6944. https://doi.org/10.3390/molecules26226944

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