Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Sharma, Raman; Lawrenson, Alexandre S.; Fisher, Nicholas; Warman, Ashley J.; Shone, Alison E.; Hill, Andrew; Mbekeani, Alison; Pidathala, Chandrakala; Amewu, Richard K.; Leung, Suet C.; Gibbons, Peter; Hong, David W.; Stocks, Paul A.; Nixon, Gemma L.; Chadwick, James; Shearer, Joanne; Gowers, Ian; Cronk, David; Parel, Serge P.; O’Neill, Paul M.; Ward, Stephen A.; Biagini, Giancarlo A.; Berry, Neil G.

doi:10.1021/jm3001482

Cited by 22 publications

(16 citation statements)

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“…Very recently, selection of resistant P . falciparum parasites by treatment with CK-2-68 and RYL-552, reported “PfNDH2 specific” inhibitors, generated mutations in the mtDNA encoded cyt b locus, while no mutations were found in PfNDH2 [29]; these data strongly suggests that CK-2-68 and RYL-552 exert their antimalarial activity by inhibiting the parasite bc 1 complex, not PfNDH2, in contrast to previous suggestions [21–23]. Clearly, the idea that PfNDH2 is a promising antimalarial drug target has been challenged with these studies [28, 29].…”

Section: Introductionmentioning

confidence: 70%

“…Based on these results [9, 10, 18], it became widely accepted that PfNDH2 could be an attractive antimalarial drug target. As a result, a significant drug discovery campaign based on high throughput screening was undertaken to seek HDQ-like inhibitors to specifically inhibit PfNDH2 [21–23], yielding the lead compound, CK-2-68 [22]. Recently, the crystal structure of PfNDH2 was resolved via X-ray crystallization [24], which could further encourage drug development efforts towards PfNDH2 using approaches based on in silico docking and structure activity relationships of PfNDH2 and its inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages

Ganesan

Dass

et al. 2019

PLoS ONE

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The battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum , the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase (NDH2) of P . falciparum , PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P . falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite’s susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc 1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc 1 complex. Our results suggest that PfNDH2 is not likely a good antimalarial drug target.

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Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages

Ganesan

Dass

et al. 2019

PLoS ONE

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“…Using GOLD and the methods developed in our group 25 compounds were docked into the binding site. We observed that our potent inhibitors, 9 and 17, were predicted to bind tightly to the Q i site with the average PLPscores of 64 and 61, respectively.…”

Section: Molecular Modelingmentioning

confidence: 99%

2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

et al. 2015

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A series of 2-pyridylquinolones has been prepared in 5-7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potential for off-target toxicity and improved metabolic stability profiles. Docking studies performed with a homology model of the Pfbc1 complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors. Page 1 of 13 MedChemComm MedChemComm Accepted Manuscript IntroductionMalaria is caused by parasites of the genus Plasmodium which are widespread in tropical and subtropical regions of the world and is responsible for one million deaths every year 1 . Plasmodium falciparum is the most deadly form of the parasite transmitted to the human host by Anopheles mosquitoes 2 and has developed resistance to many of the established classes of drugs 3 . Due to drug resistance, the discovery of novel drug candidates remains a top priority. The development of compounds focused on hitting new targets is seen as a viable way forward and is an established approach to avoid cross resistance with available antimalarials 4 . There are a large number of recent studies based on the development of antimalarials with quinolone-related structures [5][6][7] . One of these programmes resulted in the discovery of ELQ-300, a selective cytochrome bc 1 inhibitor now in pre-clinical development [8][9][10] . Our recent work has shown that inhibition of two mitochondrial enzymes in the electron transport chain -the cytochrome bc 1 complex and the recently identified PfNDH2 (Type II NADH:ubiquinone oxidoreductase) 11, 12 -results in the collapse of the mitochondrial membrane potential and to the inhibition of de novo pyrimidine biosynthesis and ultimately parasite death 13. Since effective dual inhibition of these proteins can be observed with the 2-aryl and 2-pyridylquinolone pharmacophore 14a a number of inhibitors based on this structure have been identified. Two such lead compounds are CK-2-68 and SL-2-25 (1) -both of which confer potent nanomolar activity against asexual and liver stages of P. falciparum 15,16 ( Figure 1). Here, we describe further modifications of the quinolone A-ring and 2-pyridyl side chain with the aim of reducing lipophilicity in an attempt to provide compounds with improved activity/solubility profiles.In order to increase polarity of our quinolone hit series we incorporated a hydroxyl group into the A-ring at one of the 6, 7 or 8-positions. The inclusion of the hydroxyl group in the quinolone A-ring offered the option of exploring pro-drugs for the series by derivatisation to provide either phosphate or carbamate pro-drugs. Since the corresponding methoxy analogues were prepared en route to 23 -25, these compounds were also screened against Plasmodium falciparum. Results and discussionThe synthesis of the methoxy and hydroxy series was accomplished in 5-7 steps from commercia...

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“…integrate information related to the physicochemical properties of compounds and their biological activities, in order to identify novel drug candidates [12][13][14]. Chemoinformatics has been applied to aid antiparasitic drug discovery [15][16][17], including the search for potential antileishmanial compounds through distinct approaches [18][19][20].…”

Section: Chemoinformatic Approaches Can Be Used To Analyze Andmentioning

confidence: 99%

Systematic search for benzimidazole compounds and derivatives with antileishmanial effects

et al. 2018

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Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold. Our analysis revealed that a limited number of studies had investigated the antileishmanial effects of benzimidazoles. Among this limited number, L. major was the species most commonly used to evaluate the antileishmanial effects of these compounds, whereas L. amazonensis and L. braziliensis were used least often in the reported studies. The antileishmanial activities of benzimidazole derivatives were notably variable, a fact that may depend on the substitution pattern of the scaffold. In addition, we investigated the effects of a benzimidazole derivative on promastigotes and amastigotes of L. infantum and L. amazonensis using a novel fluorometric method. Significant antileishmanial effects were observed on both species, with L. amazonensis being the most sensitive. To the best of our knowledge, this chemoinformatic analysis represents the first attempt to determine the relevance of benzimidazole scaffolds for antileishmanial drug discovery using the ChEMBL database. The present findings will provide relevant information for future structure-activity relationship studies and for the investigation of benzimidazole-derived drugs as potential treatments for leishmaniasis.

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Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Cited by 22 publications

References 58 publications

Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages

Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages

2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

Systematic search for benzimidazole compounds and derivatives with antileishmanial effects

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