Browsing by Author "Pathumwadee Intharathep"

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    Evaluating how rimantadines control the proton gating of the influenza A M2-proton port via allosteric binding outside of the M2-channel: MD simulations
    (2011-04-01) Pathumwadee Intharathep; Thanyada Rungrotmongkol; Panita Decha; Nadtanet Nunthaboot; Nopphorn Kaiyawet; Teerakiat Kerdcharoen; Pornthep Sompornpisut; Supot Hannongbua; Chulalongkorn University; Mahidol University; Thaksin University; Mahasarakham University
    In order to understand how rimantadine (RMT) inhibits the proton conductance in the influenza A M2 channel via the recently proposed "allosteric mechanism", molecular dynamics simulations were applied to the M2-tetrameric protein with four RMTs bound outside the channel at the three protonation states: the 0H-closed, 1H-intermediate and 3H-open situations. In the 0H-closed state, a narrow channel with the RMT-Asp44-Trp41 H-bond network was formed, therefore the water penetration through the channel was completely blocked. The Trp41-Asp44 interaction was absent in the 1H-intermediate state, whilst the binding of RMT to Asp44 remained, which resulted in a weakened helix-helix packing, therefore the channel was partially prevented. In the 3H-open state it was found that the electrostatic repulsion from the three charged His37 residues allowed the Trp41 gate to open, permitting water to penetrate through the channel. This agreed well with the potential of the means force which is in the following order: 0H > 1H > 3H. © 2011 Informa UK, Ltd.
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    How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?
    (2009-11-01) Thanyada Rungrotmongkol; Thanyarat Udommaneethanakit; Maturos Malaisree; Nadtanet Nunthaboot; Pathumwadee Intharathep; Pornthep Sompornpisut; Supot Hannongbua; Mahidol University; Chulalongkorn University; Mahasarakham University
    To reveal the source of oseltamivir-resistance in influenza (A/H5N1) mutants, the drug-target interactions at each functional group were investigated using MD/LIE simulations. Oseltamivir in the H274Y mutation primarily loses the electrostatic and the vdW interaction energies at the -NH3+and -OCHEt2moieties corresponding to the weakened hydrogen-bonds and changed distances to N1 residues. Differentially, the N294S mutation showed small changes of binding energies and intermolecular interactions. Interestingly, the presence of different conformations of E276 positioned between the -OCHEt2group and the mutated residue is likely to play an important role in oseltamivir-resistant identification. In the H274Y mutant, it moves towards the -OCHEt2group leading to a reduction in hydrophobicity and pocket size, whilst in the N294S mutant it acts as the hydrogen network center bridging with R224 and the mutated residue S294. The molecular details have answered a question of how the H274Y and N294S mutations confer the high- and medium-level of oseltamivir-resistance to H5N1. © 2009 Elsevier B.V. All rights reserved.
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    Why amantadine loses its function in influenza M2 mutants: MD simulations
    (2009-04-27) Chittima Laohpongspaisan; Thanyada Rungrotmongkol; Pathumwadee Intharathep; Maturos Malaisree; Panita Decha; Ornjira Aruksakunwong; Pornthep Sompornpisut; Supot Hannongbua; Chulalongkorn University; Mahidol University; Rangsit University
    Molecular dynamics simulations of the drug-resistant M2 mutants, A30T, S3 IN, and L26I, were carried out to investigate the inhibition of M2 activity using amantadine (AMT). The closed and open channel conformations were examined via non- and triply protonated H37. For the nonprotonated state, these mutants exhibited zero water density in the conducting region, and AMT was still bound to the channel pore. Thus, water transport is totally suppressed, similar to the wild-type channel. In contrast, the triply protonated states of the mutants exhibited a different water density and AMT position. A30T and L26I both have a greater water density compared to the wild-type M2, while for the A30T system, AMT is no longer inside the pore. Hydrogen bonding between AMT and H37 crucial for the bioactivity is entirely lost in the open conformation. The elimination of this important interaction of these mutations is responsible for the lost of AMT's function in influenza A M2. This is different for the S 3 IN mutant in which AMT was observed to locate at the pore opening region and bond with V27 instead of S31. © 2009 American Chemical Society.