Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite <i>Plasmodium falciparum</i>

Phillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; Mazouni, Farah El; Baldwin, Jeffrey; Rathod, Pradipsinh K.

doi:10.1021/jm8001026

Cited by 197 publications

(246 citation statements)

References 34 publications

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“…1 and Table 1). PfDHODH inhibitors in this class show potent nanomolar activity against P. falciparum in vitro, with excellent correlation observed between inhibition of PfDHODH and activity against the parasite (17,18). We identified a metabolically stable derivative of this series (DSM74) that is able to suppress Plasmodium berghei infections in the malaria mouse model, providing the first proof that PfDHODH inhibitors can have anti-malarial activity in vivo (17).…”

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confidence: 86%

“…All of the residues were within the allowed section of the Ramachandran plot (supplemental Table S2). Water molecules were added if the density was stronger than 3.4 and removed if the density was weaker than 1 in the density map with ARP/warp (32 Small Molecule X-ray Structure Determination-Crystallization of DSM1 from CH 2 Cl 2 /CH 3 OH was described previously (18). DSM15, DSM16, and DSM74 were crystallized similarly to CH 2 Cl 2 .…”

Section: Gene Cloning Of Pfdhodh-n-terminally Truncatedmentioning

confidence: 99%

“…These compounds are competitive with CoQ and inhibit the CoQ-dependent oxidation of FMN while not affecting the FMN-dependent oxidation of DHO. Site-directed mutagenesis data supported a model whereby the CoQ-binding site does not overlap with the inhibitor site, but instead inhibitors either block electron transfer between FMN and CoQ or stabilize a conformation that excludes CoQ binding (18,19). Of the identified inhibitors, one promising series has emerged based on a triazolopyrimidine core structure (see Fig.…”

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confidence: 94%

“…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

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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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confidence: 86%

Section: Gene Cloning Of Pfdhodh-n-terminally Truncatedmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

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

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115

214

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“…Figure 1 displayed structure of one of the most active triazolopyrimidine analogue compound 14. Thirty-five such novel inhibitors of PfDHODH were taken from the literature [9,10] with their biological activities in terms of IC 50 values [IC 50 values, i.e., the concentration (μM) of inhibitor that produces 50% inhibition of PfDHODH], accordingly the pIC 50 (−log IC 50 ) are reported in Table 1.…”

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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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparum

Cited by 197 publications

References 34 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

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

Antimalarials

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