Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

Sodero, Ana Carolina Rennó; Abrahim-Vieira, Bárbara; Tôrres, Pedro; Pascutti, Pedro Geraldo; Garcia, Célia Regina da Silva; Ferreira, Vı́tor F.; Rocha, David R. da; Ferreira, Sabrina Baptista; Silva, Floriano Paes

doi:10.1590/0074-02760160417

Cited by 15 publications

(18 citation statements)

References 31 publications

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“…Naphthoquinones are a type of quinone that have a chemical structure based on the naphthalene ring [ 8 ]. The naphthoquinones (found in bacteria and fungi) have been extensively studied in recent years, not only because of their role in vital biochemical processes, but also due to their wide range of pharmacological properties such as antineoplastic [ 9 , 10 , 11 ], antimicrobial [ 11 , 12 ], insecticidal [ 13 ], antimalarial [ 14 ], anti-inflammatory [ 15 ] leishmanicidal [ 16 , 17 ], trypanocide [ 16 ], and antifungal [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization and Trypanocidal Activity of a Novel Pyranaphthoquinone

et al. 2017

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Chagas disease is an endemic parasitic infection that occurs in 21 Latin American countries. New therapies for this disease are urgently needed, as the only two drugs available (nifurtimox and benznidazol) have high toxicity and variable efficacy in the disease’s chronic phase. Recently, a new chemical entity (NCE) named Pyranaphthoquinone (IVS320) was synthesized from lawsone. We report herein, a detailed study of the physicochemical properties and in vitro trypanocidal activity of IVS320. A series of assays were performed for characterization, where thermal, diffractometric, and morphological analysis were performed. In addition, the solubility, permeability, and hygroscopicity of IVS320 were determined. The results show that its poor solubility and low permeability may be due to its high degree of crystallinity (99.19%), which might require the use of proper techniques to increase the IVS320’s aqueous solubility and permeability. The trypanocidal activity study demonstrated that IVS320 is more potent than the reference drug benznidazole, with IC50/24 h of 1.49 ± 0.1 μM, which indicates that IVS320 has potential as a new drug candidate for the treatment of Chagas disease.

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Section: Introductionmentioning

confidence: 99%

Characterization and Trypanocidal Activity of a Novel Pyranaphthoquinone

et al. 2017

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“…Even when yeast and P. falciparum are two different species, the cytochrome bc1 of S. Cerevisiae has been extensively used as a model because of the high sequence identity between its cytochrome bc1 and those corresponding to Plasmodium sp. Moreover, in several works, it has used this protein complex to model the action mechanism of atovaquone and others antimalarial over P. falciparum and other pathogens [41,42,43,44,45].…”

Section: Methodsmentioning

confidence: 99%

Classical QSAR and Docking Simulation of 4-Pyridone Derivatives for Their Antimalarial Activity

et al. 2018

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In this work, the minimum energy structures of 22 4-pyridone derivatives have been optimized at Density Functional Theory level, and several quantum molecular, including electronic and thermodynamic descriptors, were computed for these substrates in order to obtain a statistical and meaningful QSAR equation. In this sense, by using multiple linear regressions, five mathematical models have been obtained. The best model with only four descriptors (r2 = 0.86, Q2 = 0.92, S.E.P = 0.38) was validated by the leave-one-out cross-validation method. The antimalarial activity can be explained by the combination of the four mentioned descriptors e.g., electronic potential, dipolar momentum, partition coefficient and molar refractivity. The statistical parameters of this model suggest that it is robust enough to predict the antimalarial activity of new possible compounds; consequently, three small chemical modifications into the structural core of these compounds were performed specifically on the most active compound of the series (compound 13). These three new suggested compounds were leveled as 13A, 13B and 13C, and the predicted biological antimalarial activity is 0.02 µM, 0.03 µM, and 0.07 µM, respectively. In order to complement these results focused on the possible action mechanism of the substrates, a docking simulation was included for these new structures as well as for the compound 13 and the docking scores (binding affinity) obtained for the interaction of these substrates with the cytochrome bc1, were −7.5, −7.2, −6.9 and −7.5 kcal/mol for 13A, 13B, 13C and compound 13, respectively, which suggests that these compounds are good candidates for its biological application in this illness.

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“…6A). Surprisingly, Mito 12 -ATO (with a 12-carbon side chain) and Mito 16 -ATO (with a 16-carbon side chain) only inhibited complex I-but not complex III-driven oxygen consumption ( www.nature.com/scientificreports/ ATO is structurally similar to Q and acts as a competitive inhibitor of Q. Modelling and energy minimization studies show that ATO docks into the Qo active site stabilized by hydrophobic and hydrogen bonding interactions with the Rieske protein and the cytochromes 5,21 . Q is reduced to ubiquinol (QH2) by complexes I and II and oxidized to Q at the catalytic site of complex III.…”

Section: Inhibition Of Cytochrome Bc 1 By Ato: Stabilizing Molecular mentioning

confidence: 99%

Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

Cheng

Hardy

Topchyan

et al. 2020

Sci Rep

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The FDA-approved prophylactic antimalarial drug atovaquone (ATO) recently was repurposed as an antitumor drug. Studies show that ATO exerts a profound antiproliferative effect in several cancer cells, including breast, ovarian, and glioma. Analogous to the mechanism of action proposed in parasites, ATO inhibits mitochondrial complex III and cell respiration. To enhance the chemotherapeutic efficacy and oxidative phosphorylation inhibition, we developed a mitochondria-targeted triphenylphosphonium-conjugated ATO with varying alkyl side chains (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO). Results show, for the first time, that triphenylphosphonium-conjugated ATO potently enhanced the antiproliferative effect of ATO in cancer cells and, depending upon the alkyl chain length, the molecular target of inhibition changes from mitochondrial complex III to complex I. Mito4-ATO and Mito10-ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito12-ATO and Mito16-ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.

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Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

Cited by 15 publications

References 31 publications

Characterization and Trypanocidal Activity of a Novel Pyranaphthoquinone

Characterization and Trypanocidal Activity of a Novel Pyranaphthoquinone

Classical QSAR and Docking Simulation of 4-Pyridone Derivatives for Their Antimalarial Activity

Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

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