千葉工業大学 / 応用化学科 / 山本研究室
計算化学で生命・物質・環境・教育の問題解決
投稿:21-12-18

Mohini Yadav, Pacifichem (2021)

題名

Theoretical insights into the dynamic correlation between the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus using dynamic residue interaction network analysis

学会

Pacifichem 2021, オンライン, ポスター発表

発表者

Mohini Yadav / 五十嵐 学(1) / 山本 典史

  1. 北海道大学 人獣共通感染症リサーチセンター

概要

Influenza is a highly infectious respiratory disease caused by influenza virus, resulting in mild to severe illness and even death. Influenza virus glycoproteins, hemagglutinin (HA) and neuraminidase (NA), play vital role in its replication process. HA helps in entry into the host cell, whereas NA helps in exit from the host cell.

Both HA and NA can be used as target for anti-influenza drug development. Oseltamivir (OTV) is a leading anti-NA drug used in the treatment and prevention of influenza. But OTV-resistant strains are emerging rapidly.

One of the major OTV-resistant strain exhibits His-to-Tyr mutation at position 274 (H274Y) in NA. However, the molecular mechanism by which OTV binding affinity is reduced to NA-H274Y mutant have not been fully elucidated.

In this study, we used the molecular dynamics simulation based dynamic residue interaction network (dRIN) analysis to investigate the correlation between OTV binding site and H274Y mutation site of H5N1 NA. dRIN analysis revealed that the OTV binding site of NA and its H274Y mutation site interact via the three interface residues connecting both sites.

Due to NA-H274Y mutation, the interaction between the residue 274 and three interface residues increased significantly, resulting in significant decrease in the interaction between OTV and its surrounding 150-loop residues. Thus, we concluded that such changes in residue interactions could reduce the OTV binding affinity to NA-H274Y mutant.

Using dRIN analysis, we succeeded in understanding the characteristic changes in residue interactions due to NA-H274Y mutation, which can elucidate the molecular mechanism of reduction in binding affinity of OTV to NA.

Finally, the dRIN analysis used in this study can be vastly applied to various systems such as individual proteins, protein-protein complexes, and protein-ligand complexes to characterize the dynamic aspects of the interactions.

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