Probing molecular mechanism of inhibitor bindings to bromodomain-containing protein 4 based on molecular dynamics simulations and principal component analysis

Wu, Shao-Ling; Wang, L F; Sun, Haibo; Wang, W; Yu, Y X

doi:10.1080/1062936x.2020.1777584

Cited by 16 publications

(7 citation statements)

References 100 publications

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“…The first two principal components corresponded to the first two eigenvectors of the covariance matrix. The PCA scatter plots were then constructed with Matplotlib [ 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus

et al. 2022

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The use of vaccinations and antiviral medications have gained popularity in the therapeutic management of avian influenza H7N9 virus lately. Antiviral medicines are more popular due to being readily available. The presence of the neuraminidase protein in the avian influenza H7N9 virus and its critical role in the cleavage of sialic acid have made it a target drug in the development of influenza virus drugs. Generally, the neuraminidase proteins have common conserved amino acid residues and any mutation that occurs around or within these conserved residues affects the susceptibility and replicability of the influenza H7N9 virus. Herein, we investigated the interatomic and intermolecular dynamic impacts of the experimentally reported E119V mutation on the oseltamivir resistance of the influenza H7N9 virus. We extensively employed molecular dynamic (MD) simulations and subsequent post-MD analyses to investigate the binding mechanisms of oseltamivir-neuraminidase wildtype and E119V mutant complexes. The results revealed that the oseltamivir-wildtype complex was more thermodynamically stable than the oseltamivir-E119V mutant complex. Oseltamivir exhibited a greater binding affinity for wildtype (−15.46 ± 0.23 kcal/mol) relative to the E119V mutant (−11.72 ± 0.21 kcal/mol). The decrease in binding affinity (−3.74 kcal/mol) was consistent with RMSD, RMSF, SASA, PCA, and hydrogen bonding profiles, confirming that the E119V mutation conferred lower conformational stability and weaker protein–ligand interactions. The findings of this oseltamivir-E119V mutation may further assist in the design of compounds to overcome E119V mutation in the treatment of influenza H7N9 virus patients.

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“…The first two principal components corresponded to the first two eigenvectors of the covariance matrix. The PCA scatter plots were then constructed with Matplotlib [ 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus

et al. 2022

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“…The first two principal components correspond to the first two Eigenvectors of the covariance matrix. PCA scatter plots were then constructed using Matplotlib [ 57 , 58 ].…”

Section: Methodsmentioning

confidence: 99%

Impact of the R292K Mutation on Influenza A (H7N9) Virus Resistance towards Peramivir: A Molecular Dynamics Perspective

2022

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In March 2013, a novel avian influenza A (H7N9) virus emerged in China. By March 2021, it had infected more than 1500 people, raising concerns regarding its epidemic potential. Similar to the highly pathogenic H5N1 virus, the H7N9 virus causes severe pneumonia and acute respiratory distress syndrome in most patients. Moreover, genetic analysis showed that this avian H7N9 virus carries human adaptation markers in the hemagglutinin and polymerase basic 2 (PB2) genes associated with cross-species transmissibility. Clinical studies showed that a single mutation, neuraminidase (NA) R292K (N2 numbering), induces resistance to peramivir in the highly pathogenic H7N9 influenza A viruses. Therefore, to evaluate the risk for human public health and understand the possible source of drug resistance, we assessed the impact of the NA-R292K mutation on avian H7N9 virus resistance towards peramivir using various molecular dynamics approaches. We observed that the single point mutation led to a distorted peramivir orientation in the enzyme active site which, in turn, perturbed the inhibitor’s binding. The R292K mutation induced a decrease in the interaction among neighboring amino acid residues when compared to its wild-type counterpart, as shown by the high degree of fluctuations in the radius of gyration. MM/GBSA calculations revealed that the mutation caused a decrease in the drug binding affinity by 17.28 kcal/mol when compared to the that for the wild-type enzyme. The mutation caused a distortion of hydrogen bond-mediated interactions with peramivir and increased the accessibility of water molecules around the K292 mutated residue.

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“…The complexes of the three inhibitors and BRD4 were performed by Amber 16 software with 150 ns molecular dynamics simulations (The sufficiency to really reach the proper equilibrium of the MD simulation needs to be explored according to the characteristics of the system. We have found these papers for the BET family with MD simulations for 100–200 ns [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In this study, the 150 ns MD simulations were performed).…”

Section: Methodsmentioning

confidence: 99%

Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors

Chen

Geng

et al. 2021

Molecules

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Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.

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Probing molecular mechanism of inhibitor bindings to bromodomain-containing protein 4 based on molecular dynamics simulations and principal component analysis

Cited by 16 publications

References 100 publications

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus

Impact of the R292K Mutation on Influenza A (H7N9) Virus Resistance towards Peramivir: A Molecular Dynamics Perspective

Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors

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