An exclusive computational insight toward molecular mechanism of MMV007571, a multitarget inhibitor of<i>Plasmodium falciparum</i>

Rawat, Ravi; Verma, Saurabh

doi:10.1080/07391102.2019.1700165

Cited by 18 publications

(5 citation statements)

References 29 publications

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“…tuberculosis. We have also included two antimalarial compounds from the literature: MMV007571 − and XCV (Figure ), which are supposed to target the cytochrome bc1 complex and/or the dihydroorotate dehydrogenase (DHODH). The docking scores of all compounds regarding these two mitochondrial targets were also evaluated, and the obtained values are summarized in Table .…”

Section: Results and Discussionmentioning

confidence: 99%

“…In addition, we have also included in Table 5 the evaluated activities of simple synthons (lawsone and iodolawsone) along with the reference drugs atovaquone for P. falciparum , miltefosine for L. donovani , and streptomycin for M. tuberculosis . We have also included two antimalarial compounds from the literature: MMV007571 43 − 45 and XCV 46 ( Figure 4 ), which are supposed to target the cytochrome bc1 complex and/or the dihydroorotate dehydrogenase (DHODH). The docking scores of all compounds regarding these two mitochondrial targets were also evaluated, and the obtained values are summarized in Table 6 .…”

Section: Results and Discussionmentioning

confidence: 99%

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Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

et al. 2022

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The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

et al. 2022

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“…The dynamic behavior of the complexes was evaluated using MD simulation in the GROMACS package program (version 2022.2). [30][31][32] Pdb2gmx constructed protein topology with the CHARMM27 force field, [33] and ligand topology was generated using the SwissParam server. [34] 4.3.2 | Setting up a system for simulation…”

Section: Preparation Of Enzymementioning

confidence: 99%

Natural flavonoids as promising 6‐phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments

Adem,

Yırtıcı,

Aydın

et al. 2023

Archiv der Pharmazie

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The primary strategy in the fight against cancer is to screen compounds that may be effective on different types of cancer. Compounds from plants seem to be a good source. The present study investigated the inhibitory effects of some flavonoids on the 6‐phosphogluconate dehydrogenase (6‐PGD) enzyme. We determined that quercetin, myricetin, fisetin, morin, apigenin, and baicalein exhibited powerful inhibition effects with IC50 values between 4.08 and 21.26 µM, while luteolin, kaempferol, apiin, galangin, and baicalin showed moderate effects with IC50 values between 54.15 and 138.91 µM. Quercetin competitively inhibited the binding of NADP and 6‐phosphogluconate to the 6‐PGD enzyme with Ki values of 0.527 ± 0.251 and 0.374 ± 0.138 µM, respectively. We calculated Ki values using the Cheng–Prusoff equation as between 0.44 and 14.88 µM. The possible interaction details of polyphenols with the active site of 6‐PGD were analyzed with docking software. In silico and in vitro studies indicated that the –OH groups on the A and C ring of flavonoids bind to the enzyme's active site via hydrogen bonding, while the –OH groups on the C ring contributed significantly to the increase in the inhibitory potentials of the molecules. Molecular dynamic simulations tested the stability of the 6‐PGD‐quercetin complex during 100 ns. These phytochemicals were suitable for drug use when optimized with absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The effects of the studied compounds on cancer cell lines of potential targets were demonstrated by network analysis. In conclusion, this study suggests that flavonoids found to be potent inhibitors could serve as leading candidates to treat many cancers via 6‐PGD inhibition.

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“…Alternative profiles have emerged in metabolomic studies that correlate to innovative targets that do not yet have validated clinical efficiency. Such is the case of MMV007571 and MMV020439 that were shown through untargeted metabolomics to inhibit new permeation pathways (NPP), along with pyrimidine synthesis and the mitETC (Dickerman et al 2016;Rawat and Verma 2020). Since NPP may be redundant in importing and exporting nutrients and waste products, it is difficult to link a metabolomic fingerprint to this particular pathway, more so since the compounds also interfered with other metabolomic pathways.…”

Section: Unknown and Othersmentioning

confidence: 99%

“…Since NPP may be redundant in importing and exporting nutrients and waste products, it is difficult to link a metabolomic fingerprint to this particular pathway, more so since the compounds also interfered with other metabolomic pathways. However, NPP are recognized potential antimalarial targets, as they are induced by the parasite and important for its viability (Dickerman et al 2016;Rawat and Verma 2020). Another alternative profile that has emerged is associated with the acetyl CoA anabolism.…”

Section: Unknown and Othersmentioning

confidence: 99%

Recent metabolomic developments for antimalarial drug discovery

et al. 2022

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Malaria is a parasitic disease that remains a global health issue, responsible for a significant death and morbidity toll. Various factors have impacted the use and delayed the development of antimalarial therapies, such as the associated financial cost and parasitic resistance. In order to discover new drugs and validate parasitic targets, a powerful omics tool, metabolomics, emerged as a reliable approach. However, as a fairly recent method in malaria, new findings are timely and original practices emerge frequently. This review aims to discuss recent research towards the development of new metabolomic methods in the context of uncovering antiplasmodial mechanisms of action in vitro and to point out innovative metabolic pathways that can revitalize the antimalarial pipeline.

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An exclusive computational insight toward molecular mechanism of MMV007571, a multitarget inhibitor ofPlasmodium falciparum

Cited by 18 publications

References 29 publications

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

Natural flavonoids as promising 6‐phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments

Recent metabolomic developments for antimalarial drug discovery

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