The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

Heikkila, T.; Thirumalairajan, Srinath; Davies, Michelle; Parsons, Mark R.; McConkey, Glenn A.; Fishwick, Colin W. G.; Johnson, A. Peter

doi:10.1016/j.bmcl.2005.09.045

Cited by 60 publications

(41 citation statements)

References 19 publications

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“…This flexibility is likely to underlie the finding that multiple inhibitor series have been reported for PfDHODH that sample diverse chemical space (17,18,(21)(22)(23)(24). Although the triazolopyrimidine derivatives interact with the Pfnaphthyl pocket, other identified inhibitors are likely to bind to the PfA77 phenyl pocket, explaining how the enzyme can accommodate these wide ranging scaffolds.…”

Section: Discussionmentioning

confidence: 99%

“…This has led to a substantial effort to target PfDHODH for drug discovery programs and to the identification of diverse scaffolds showing species-selective inhibition of the enzyme (17,18,(21)(22)(23)(24). The prior structure of PfDHODH complexed to A77 1726 (14), a hDHODH-specific inhibitor with poor affinity for PfDHODH (19), neither explains the ability of PfDHODH to bind the array of identified inhibitors nor provides an understanding of the developing SAR for the triazolopyrimidine-based inhibitor series.…”

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confidence: 99%

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Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Deng

Gujjar

Mazouni

et al. 2009

Journal of Biological Chemistry

115

214

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Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into speciesselective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.The human malaria parasite is endemic in 87 countries putting 2.5 billion people in the poorest nations of the tropics at risk for the disease (1, 2). Despite intensive efforts to control malaria through combination drug therapy and insect control programs, malaria remains one of the largest global health problems. The most severe form of the disease is caused by Plasmodium falciparum, which kills 1-2 million people yearly, primarily children and pregnant woman. Effective vaccines have not been developed, and chemotherapy remains the mainstay of both treatment and prevention of the disease. Unfortunately widespread drug resistance to almost every known antimalarial agent has compromised the effectiveness of malaria control programs (3). The introduction of artemisinin combination chemotherapy has provided new treatment options to combat drug-resistant parasites (4). However, recent reports by the World Health Organization suggest that resistance to artemisinin is developing along the Thai-Cambodian border, underscoring the need for a continual pipeline of new drug development to combat this disease.The malaria parasite relies exclusively on de novo pyrimidine biosynthesis to supply precursors for DNA and RNA biosynthesis (5, 6). In contrast, the human host cells contain the enzymatic machinery for both de novo pyrimidine biosynthesis and for salvage of preformed pyrimidine bases and nucleosides. The lack of a redundant mechanism to acquire pyrimidines in malaria...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Deng

Gujjar

Mazouni

et al. 2009

Journal of Biological Chemistry

115

214

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“…Hence, PfDHODH can be exploited as a novel drug target for development of new antimalarial agents (Heikkila et al, 2007). Several derivatives of triazolopyrimidine (Phillips et al, 2008;Gujjar et al, 2009), benzanilide (Baldwin et al, 2005;Heikkila et al, 2006), naphthamide and urea (Baldwin et al, 2005) have been reported to inhibit PfDHODH. Yet, there is a good scope for design and/or optimization of these molecules owing to either (a) their toxic nature, e.g.…”

Section: P Falciparum Dihydroorotate Dehydrogenase (Pfdhodh)mentioning

confidence: 99%

Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

2010

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The search for new antimalarial agents is necessary as current drugs in the market have become vulnerable due to the emergence of resistant strains of Plasmodium falciparum (Pf). The enzyme dihydroorotate dehydrogenase (PfDHODH) is a validated target for development of antimalarial agents. PfDHODH is a crucial enzyme in the de novo pyrimidine biosynthesis pathway and is essential for the growth of the parasite. In this article, we report the design, synthesis and evaluation of benzanilides as inhibitors of PfDHODH. From the pool of molecules designed using molecular modeling techniques, candidates were shortlisted for further evaluation based on docking scores and 3D-QSAR studies. The activities of these shortlisted analogs were predicted from CoMFA and CoMSIA models. The most promising molecules were synthesized using solvent-free microwave-assisted synthesis and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity by the whole cell assay method. Two molecules viz. KMC-3 and KMC-15 were found to be active at 8.7 and 5.7 lM concentrations, respectively.

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“…Unlike mammalian cells, which contain enzymes for both de novo biosynthesis and salvage of preformed pyrimidine bases and nucleosides, the parasite relies exclusively on de novo synthesis. Dihydroorotate dehydrogenase is fourth enzyme in the pyrimidine biosynthetic pathway [5]. Dihydroorotate dehydrogenase is a mitochondrially localized flavoenzyme, which catalyzes the rate-limiting step of the oxidation of dihydroorotate (DHO) to orotate in the presence of the co-factors flavin mononucleotide (FMN) and ubiquinone (CoQ) in de novo pyrimidine biosynthesis pathway and is therefore an attractive antimalarial chemotherapeutic target [4].…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods

Shah

Kumar

Tiwari³

et al. 2012

J Chem Biol

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A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking and 3D quantitative structure-activity relationship studies. Genetic algorithm-based criteria was adopted for selection of training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model development and validation. Both the comparative molecular field analyses (q 2 LOO ¼ 0:841, r 2 ncv ¼ 0:99) and comparative molecular similarity indices analyses (q 2 LOO ¼ 0:757, r 2 ncv ¼ 0:943) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules and will assist in the design of more potent inhibitors of PfDHODH.

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The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

Cited by 60 publications

References 19 publications

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Structural Plasticity of Malaria Dihydroorotate Dehydrogenase Allows Selective Binding of Diverse Chemical Scaffolds

Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods

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