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Research Article

Efficiency of membrane fusion inhibitors on different hemagglutinin subtypes: insight from a molecular dynamics simulation perspective

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Received 20 Dec 2023, Accepted 19 Feb 2024, Published online: 28 Feb 2024
 

Abstract

The challenge in vaccine development, along with drug resistance issues, has encouraged the search for new anti-influenza drugs targeting different viral proteins. Hemagglutinin (HA) glycoprotein, crucial in the viral replication cycle, has emerged as a promising therapeutic target. CBS1117 and JNJ4796 were reported to exhibit similar potencies against infectious group 1 influenza, which included H1 and H5 HAs; however, their potencies were significantly reduced against group 2 HA. This study aims to explore the molecular binding mechanisms and group specificity of these fusion inhibitors against both group 1 (H5) and group 2 (H3) HA influenza viruses using molecular dynamics simulations. CBS1117 and JNJ4796 exhibit stronger interactions with key residues within the H5 HA binding pocket compared to H3-ligand complexes. Hydrogen bonding and hydrophobic interactions involving residues, such as H381, Q401, T3251 (H5-CBS1117), T3181 (H5-JNJ4796), W212, I452, V482, and V522 predominantly contribute to stabilizing H5-ligand systems. In contrast, these interactions are notably weakened in H3-inhibitor complexes. Predicted protein-ligand binding free energies align with experimental data, indicating CBS1117 and JNJ4796's preference for heterosubtypic group 1 HA binding. Understanding the detailed atomistic mechanisms behind the varying potencies of these inhibitors against the two HA groups can significantly contribute to the development and optimization of effective HA fusion inhibitors. To accomplish this, the knowledge of the transition of HA from its pre- to post-fusion states, the molecular size of ligands, and their potential binding regions, could be carefully considered.

Communicated by Ramaswamy H. Sarma

Acknowledgments

Supramolecular Chemistry Research Unit (Mahasarakham University) and the Structural and Computational Biology Research Unit (Chulalongkorn University) are acknowledged for computational facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research project was financially supported by the Thailand Science Research and Innovation (TSRI). N.N. would like to thank the Center of Excellence for Innovation in Chemistry (PERCH-CIC) for financial support.

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