Exploring the impact of H5N1 neuraminidase (H274Y) mutation on Peramivir: a bio-computational study from a molecular perspective

Buthelezi, Ndumiso M.; Mhlongo, Ndumiso N.; Amoako, Daniel G.; Somboro, Anou M.; Sosibo, Sphelele C.; Shunmugam, Letitia; Machaba, Kgothatso E; Kumalo, Hezekiel M.

doi:10.1080/07391102.2019.1677501

Cited by 6 publications

(10 citation statements)

References 12 publications

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“…The energy decomposition analysis revealed that Arg117, Arg224, and Arg292 contributed the largest residual energy to Peramivir binding to wild type, I222K, H274Y, and H274Y-I222K mutants, as shown in Figure 6. This is also in accordance with our previous study, which indicated that these residues contributed significantly to Peramivir binding to wild type and mutant H274K [18]. It is thought that these residues play a crucial role in forming the binding pocket between Peramivir and neuraminidase.…”

Section: Per-residue Interaction Energy Decomposition Analysissupporting

confidence: 93%

Molecular Dynamic Investigation of H5N1 Influenza Virus Dual H274Y-I222K Mutation Resistance to Peramivir

Buthelezi

Mtambo²,

Amoako

et al. 2022

Preprint

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In light of the rapid rise of an influenza pandemic, the constant genetic mutations of H5N1 influenza viruses pose a threat. Mutations at the sialic site are often responsible for multiple drug resistance. To design effective new inhibitors, it is necessary to undertake research into the mechanism of resistance of influenza viruses and their rapid mutations. The molecular dynamic simulation technique has been an instrumental tool in understanding how proteins function from an atomic perspective. A thorough investigation has not been conducted using molecular dynamics to examine the impact of these mutations (I222K, H274Y, and H274Y-I222K) on Peramivir. This study investigates the effects of I222K, H274Y, H274Y-I222K substitution on the neuraminidase–Peramivir complex and identifies responsible residues for complex conformations. The mutations caused distorted Peramivir orientation in the enzyme active site, which affected the inhibitor’s binding. In the presence of various mutations, interaction between protein and ligand became less thermodynamically favorable. We observed the following trend in binding free energy difference: WT<I222<H274Y<H274Y-I222K. As a result of the thermodynamic instability of the mutant complexes, Peramivir’s potency is reduced due to impaired binding interactions. Wild type complex displays thermodynamic stability and strong protein-ligand interactions due to their high total energy contributions and low residue flexibility. Based on the energy decomposition analysis, Arg117, Arg224, and Arg292 contributed the largest residual energy for the binding of Peramivir to wild type and mutants. These residues are thought to play a key role in the formation of the binding pocket between Peramivir and neuraminidase. This study provides a basis for investigating the effects of other mutations on Peramivir’s efficacy against the H5N1 virus.

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Section: Per-residue Interaction Energy Decomposition Analysissupporting

confidence: 93%

Molecular Dynamic Investigation of H5N1 Influenza Virus Dual H274Y-I222K Mutation Resistance to Peramivir

Buthelezi

Mtambo²,

Amoako

et al. 2022

Preprint

Self Cite

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“…The original static RIN and its extended version, dRIN, have been used in various analyses such as protein stability (Brinda & Vishveshwara, 2005;Giollo et al, 2014), allosteric behavior (Sethi et al, 2009) and drug resistance (Xue et al, 2012;Bhakat, Martin & Soliman, 2014;Xue et al, 2014;Zhang et al, 2019). Recently, Buthelezi et al (2019) used RIN analysis to obtain a molecular perspective of drug resistance in influenza viruses with H274Y mutation in NA; however, they only examined the changes in residue interactions with the mutation based on static RINs constructed from representative average structures obtained via MD simulations (Buthelezi et al, 2019). Overall, the mechanism by which drug resistance conferring H274Y mutation in NA of influenza virus affects the dynamic behavior of residue interactions remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus

Yadav

Igarashi

Yamamoto

2021

PeerJ

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Background Oseltamivir (OTV)-resistant influenza virus exhibits His-to-Tyr mutation at residue 274 (H274Y) in N1 neuraminidase (NA). However, the molecular mechanisms by which the H274Y mutation in NA reduces its binding affinity to OTV have not been fully elucidated. Methods In this study, we used dynamic residue interaction network (dRIN) analysis based on molecular dynamics simulation to investigate the correlation between the OTV binding site of NA and its H274Y mutation site. Results dRIN analysis revealed that the OTV binding site and H274Y mutation site of NA interact via the three interface residues connecting them. H274Y mutation significantly enhanced the interaction between residue 274 and the three interface residues in NA, thereby significantly decreasing the interaction between OTV and its surrounding loop 150 residues. Thus, we concluded that such changes in residue interactions could reduce the binding affinity of OTV to NA, resulting in drug resistant influenza viruses. Using dRIN analysis, we succeeded in understanding the characteristic changes in residue interactions due to H274Y mutation, which can elucidate the molecular mechanism of reduction in OTV binding affinity to influenza NA. Finally, the dRIN analysis used in this study can be widely applied to various systems such as individual proteins, protein-ligand complexes, and protein-protein complexes, to characterize the dynamic aspects of the interactions.

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“…In recent years, the radius of gyration has been applied to give insight into the level of compactness of the protein structure throughout the simulation [ 29 ]. To measure the level of compactness of the protein structure, Rg was calculated, and the results are presented in Figure 7 with the average Rg values ranging from 24.63–25.73 Å.…”

Section: Resultsmentioning

confidence: 99%

In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

2022

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Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.

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Exploring the impact of H5N1 neuraminidase (H274Y) mutation on Peramivir: a bio-computational study from a molecular perspective

Cited by 6 publications

References 12 publications

Molecular Dynamic Investigation of H5N1 Influenza Virus Dual H274Y-I222K Mutation Resistance to Peramivir

Molecular Dynamic Investigation of H5N1 Influenza Virus Dual H274Y-I222K Mutation Resistance to Peramivir

Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus

In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

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