The global motion affecting electron transfer in <i>Plasmodium falciparum</i> type II NADH dehydrogenases: a novel non-competitive mechanism for quinoline ketone derivative inhibitors

Xie, Tao; Wu, Zhixiang; Gu, Junping; Guo, Runyu; Yan, Xiaohong; Duan, Huaichuan; Liu, Xinyu; Liu, Wei; Liang, Li; Wan, Hua‐Ping; Luo, Yafei; Tang, Dianyong; Shi, Hubing; Hu, Jianping

doi:10.1039/c9cp02645b

Cited by 9 publications

(3 citation statements)

References 72 publications

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“…If the Δ G HD o (XRH •+ ) values of 17 XRH •+ are compared with that of their parent Hantzsch ester radical cations (denoted as HEH 2 •+ , Δ G HD o (HEH 2 •+ ) = 25.28 kcal/mol, calculated in this work) without any substituent in the 4-position (Figure ), 3RH •+ , 8RH •+ , 11RH •+ , 13RH •+ , and 14RH •+ have larger Δ G HD o (XRH •+ ) values (25.64–31.25 kcal/mol) than HEH 2 •+ , while others have smaller Δ G HD o (XRH •+ ) values (19.35–24.71 kcal/mol) than HEH 2 •+ (25.28 kcal/mol). It is well known that NADH (Scheme ), which has the typical 1,4-dihydropyridine structure in the redox core same as XRH and HEH 2 , − is an important redox coenzyme as a hydrogen and electron carrier in vivo. − Figure also presents Δ G HD o (NADH •+ ) (23.90 kcal/mol, computed in this work), which was clearly lower than the Δ G HD o (HEH 2 •+ ) value (25.28 kcal/mol), even though they all have the 1,4-dihydropyridine structure. Δ G HD o (NADH •+ ) (23.90 kcal/mol) is rightly among the range of 17 Δ G HD o (XRH •+ ) values (19.35–31.25 kcal/mol).…”

Section: Resultsmentioning

confidence: 56%

Quantitative Estimation of the Hydrogen-Atom-Donating Ability of 4-Substituted Hantzsch Ester Radical Cations

et al. 2021

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The purpose of this study is to investigate thermodynamic and kinetic properties on the hydrogen-atom-donating ability of 4-substituted Hantzsch ester radical cations (XRH •+ ), which are excellent NADH coenzyme models. Gibbs free energy changes and activation free energies of 17 XRH •+ releasing H • [denoted as Δ G HD o (XRH •+ ) and Δ G HD ≠ (XRH •+ )] were calculated using density functional theory (DFT) and compared with that of Hantzsch ester (HEH 2 ) and NADH. Δ G HD o (XRH •+ ) range from 19.35 to 31.25 kcal/mol, significantly lower than that of common antioxidants (such as ascorbic acid, BHT, the NADH coenzyme, and so forth). Δ G HD ≠ (XRH •+ ) range from 29.81 to 39.00 kcal/mol, indicating that XRH •+ spontaneously releasing H • are extremely slow unless catalysts or active intermediate radicals exist. According to the computed data, it can be inferred that the Gibbs free energies and activation free energies of the core 1,4-dihydropyridine radical cation structure (DPH •+ ) releasing H • [Δ G HD o (DPH •+ ) and Δ G HD ≠ (DPH •+ )] should be 19–32 kcal/mol and 29–39 kcal/mol in acetonitrile, respectively. The correlations between the thermodynamic driving force [Δ G HD o (XRH •+ )] and the activation free energy [Δ G HD ≠ (XRH •+ )] are also explored. Gibbs free energy is the important and decisive parameter, and Δ G HD ≠ (XRH •+ ) increases in company with the increase of Δ G HD o (XRH •+ ), but no simple linear correlations are found. Even though all XRH •+ are judged as excellent antioxidants from the thermodynamic view, the computed data indicate that whether XRH •+ is an excellent antioxidant in reaction is decided by the R substituents in 4-position. XRH •+ with nonaromatic substituents tend to release R • instead of H • to quench radicals. XRH •+ with aromatic substituents tend to release H • and be used as antioxidants, but not all aromatic substituted Hantzsch esters are excellent antioxidants.

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Section: Resultsmentioning

confidence: 56%

Quantitative Estimation of the Hydrogen-Atom-Donating Ability of 4-Substituted Hantzsch Ester Radical Cations

et al. 2021

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“…Here, the initial conformation of inhibitor SQ109 molecule comes from the complex crystal structure 6AJG. During molecular docking experiment, Lamarckian genetic algorithm (LGA) 51 combined with local energy search method was used to optimize binding conformations, and a semi-empirical potential function was adopted as the energy scoring function [52][53][54] . The rectangular docking box with side length of 40 Å and grid spacing of 0.375 Å was generated, with its center (100.69, 15.41, 32.12) being preset.…”

Section: Molecular Docking Experimentsmentioning

confidence: 99%

S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism

Ge,

Luo,

Liu

et al. 2024

J Mol Model

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Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows signi cant resistance to the inhibitor SQ109, while the speci c action mechanism remains unclear. In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics and H-bond energy change of MmpL3 after S288T mutation. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport e ciency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant, but also aids the development of novel anti-tuberculosis inhibitors.

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“…• (Thorson et al, 1995;Hu et al, 2008;Xie et al, 2019). As shown in Table 2, there are two stable hydrogen bonds-G171-OE1/Y126-HH and V248-O/L103-H-in both IDO and IDO-BBJ systems, which play an important role in maintaining the stability of IDO1.…”

Section: Hydrogen Bond Analysismentioning

confidence: 99%

Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations

Liu

Zhang

Duan

et al. 2020

Front. Mol. Biosci.

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The global motion affecting electron transfer in Plasmodium falciparum type II NADH dehydrogenases: a novel non-competitive mechanism for quinoline ketone derivative inhibitors

Abstract: The association of RYL-552 results in the weakening of intramolecular hydrogen bonds and large allosterism of NDH2. And there was a significant positive correlation between the angular change and the distance change.

Cited by 9 publications

References 72 publications

Quantitative Estimation of the Hydrogen-Atom-Donating Ability of 4-Substituted Hantzsch Ester Radical Cations

Quantitative Estimation of the Hydrogen-Atom-Donating Ability of 4-Substituted Hantzsch Ester Radical Cations

S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism

Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations

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