From crystal to compound: structure-based antimalarial drug discovery

Drinkwater, N.; McGowan, Sheena

doi:10.1042/bj20140240

Cited by 22 publications

(14 citation statements)

References 264 publications

(373 reference statements)

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“…This places the progress in the fight against the disease under pressure, especially since there is no effective vaccine against malaria (3). Several new drug targets have been identified in recent years (4); however, these targets now need to be exploited through the development of directed treatments.…”

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confidence: 99%

A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

Macuamule

Tjhin

Jana

et al. 2015

Antimicrob Agents Chemother

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cPantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC 50 ], ϳ20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of ␣-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC 50 , 52 ؎ 6 nM), target specificity, and low toxicity.O ne-half of the world's population (ϳ3.4 billion people) is at risk of contracting malaria, with pregnant women and children Ͻ5 years of age being especially vulnerable. In 2013, the WHO estimated that malaria caused ϳ584,000 deaths globally, with the majority occurring in Africa (1). Although efforts to control and to eliminate malaria in the past 15 years have saved an estimated 3.3 million lives (1), drug-resistant parasites continue to emerge (2). This places the progress in the fight against the disease under pressure, especially since there is no effective vaccine against malaria (3). Several new drug targets have been identified in recent years (4); however, these targets now need to be exploited through the development of directed treatments.We are interested in targeting the biosynthesis of the essential cofactor coenzyme A (CoA) from the water-soluble vitamin B 5 (pantothenate, compound 1 in Fig. 1) for antimalarial drug development (5, 6). It has been shown that extracellular pantothenate is essential for intracellular malaria parasites (7), which indicates that Plasmodium falciparum does not utilize exogenous CoA but must synthesize CoA de novo (8).Pantothenate analogues interfere with the ability of P. falciparum to utilize the vitamin, with many analogues being characterized as growth inhibitors of the blood-stage parasites (9-11). Furthermore, a recent study showed that CoA biosynthesis can be targeted by a chemically diverse set of inhibitors that do not resemble pantothenate, the most potent of which had a 50% inhibitory concentration (IC 50 ; the concentration that inhibits parasite proliferation by 50%) of 120 nM against blood-stage parasites (12). These studies support pantothenate utilization (and therefore CoA biosynthesis and CoA-dependent processes) as an antiplasmodial target.Recently we showed that N-substituted pantothenamides (PanAms), a specific class of pantothenate analogues, have excellent antiplasmodial activity. Among these, N-phenethyl-pantothenamide (N-PE-PanAm) (compound 2 in Fig. 1) exhibited an IC 50 of 20 nM (13); this potency is comparable to that of chloroquine (14, 15). In practice, however, the antiplasmodial activity of the PanAms is decreased since they are degraded by pantetheinase (13), a ubiquitous enzyme of the Vanin protein family that is present in serum (16,17). Pantetheinase normally catalyzes the hydrolysis of pantetheine (a CoA-derived metabolite) to for...

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confidence: 99%

A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

Macuamule

Tjhin

Jana

et al. 2015

Antimicrob Agents Chemother

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“…The presence of bound substrates in the study of Tokuoka and coworkers enhances the value of these structures to structure-based drug design (Tokuoka et al, 2008). Indeed, in silico drug-design efforts based on these structures have been reported (Takashima et al, 2012;Drinkwater & McGowan, 2014). For both of these reasons, it is important that these structures are well determined and that the ligands are correctly identified (Touw et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Re-refinement ofPlasmodium falciparumorotidine 5′-monophosphate decarboxylase provides a clearer picture of an important malarial drug target

et al. 2018

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The development of antimalarial drugs remains a public health priority, and the orotidine 5 0 -monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) has great potential as a drug target. The crystallization of PfOMPDC with substrate bound represents an important advance for structurebased drug-design efforts [Tokuoka et al. (2008), J. Biochem. 143, 69-78]. The complex of the enzyme bound to the substrate OMP (PDB entry 2za1) would be of particular utility in this regard. However, re-refinement of this structure of the Michaelis complex shows that the bound ligand is the product rather than the substrate. Here, the re-refinement of a set of three structures, the apo enzyme and two versions of the product-bound form (PDB entries 2za1, 2za2 and 2za3), is reported. The improved geometry and fit of these structures to the observed electron density will enhance their utility in antimalarial drug design.

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“…The pharmacophore model: This screening method is mainly aimed at determining whether the molecular structure of the compound exists in the structural fragment common to the drug-like molecule [ 60 , 61 , 62 ].…”

Section: Introduce Other Prediction Methods Of Herbal Compounds Inmentioning

confidence: 99%

Prediction Methods of Herbal Compounds in Chinese Medicinal Herbs

et al. 2018

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Chinese herbal medicine has recently gained worldwide attention. The curative mechanism of Chinese herbal medicine is compared with that of western medicine at the molecular level. The treatment mechanism of most Chinese herbal medicines is still not clear. How do we integrate Chinese herbal medicine compounds with modern medicine? Chinese herbal medicine drug-like prediction method is particularly important. A growing number of Chinese herbal source compounds are now widely used as drug-like compound candidates. An important way for pharmaceutical companies to develop drugs is to discover potentially active compounds from related herbs in Chinese herbs. The methods for predicting the drug-like properties of Chinese herbal compounds include the virtual screening method, pharmacophore model method and machine learning method. In this paper, we focus on the prediction methods for the medicinal properties of Chinese herbal medicines. We analyze the advantages and disadvantages of the above three methods, and then introduce the specific steps of the virtual screening method. Finally, we present the prospect of the joint application of various methods.

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From crystal to compound: structure-based antimalarial drug discovery

Cited by 22 publications

References 264 publications

A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

Re-refinement ofPlasmodium falciparumorotidine 5′-monophosphate decarboxylase provides a clearer picture of an important malarial drug target

Prediction Methods of Herbal Compounds in Chinese Medicinal Herbs

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