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

ABSTRACT: 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 ([Formula: see text], [Formula: see text]) and comparative molecular similarity indices analyses ([Formula: see text], [Formula: see text]) 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.

SUBMITTER: Shah P

PROVIDER: S-EPMC3375378 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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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 Priyanka P Kumar Sumit S Tiwari Sunita S Siddiqi Mohammad Imran MI

Journal of chemical biology 20120205 3

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 val ...[more]

PMID: 23382788

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Project description:Genetic manipulation of Plasmodium falciparum in culture through transfection has provided numerous insights into the molecular and cell biology of this parasite. The procedure is rather cumbersome, and is limited by the number of drug-resistant markers that can be used for selecting transfected parasites. Here we report a new selectable marker that could allow multiple transfections. We have taken advantage of our finding that a critical function of the mitochondrial electron transport chain (mtETC) in the erythrocytic stages of P. falciparum is the regeneration of ubiquinone as co-substrate of dihydroorotate dehydrogenase (DHODH), and that transgenic P. falciparum expressing ubiquinone-independent DHODH from yeast (yDHODH) are resistant to all mtETC inhibitors. We assessed the possibility of using yDHODH as a positive selectable marker for transfections of P. falciparum, including its use in gene disruption strategies. We constructed a transfection vector designed for gene disruption, termed pUF-1, containing the yDHODH gene as the positive selection marker in combination with a previously described fused yeast cytosine deaminase-uracil phosphoribosyl transferase gene as a negative selection marker. Transfection of the D10 strain followed by selection with atovaquone yielded positively selected parasites containing the plasmid, demonstrating that yDHODH can be used as a selective marker. Atovaquone, however, could not be used for such selection with the Dd2 strain of P. falciparum. On the other hand, we demonstrated that yDHODH transgenic parasites could be selected in both strains by Plasmodium DHODH-specific triazolopyrimidine-based inhibitors. Thus, selection with DHODH inhibitors was superior in that it successfully selected transgenic Dd2 parasites, as well as yielded transgenic parasites after a shorter period of selection. As a proof of concept, we have successfully disrupted the type II vacuolar proton-pumping pyrophosphatase gene (PfVP2) in P. falciparum by double crossover recombination, showing that this gene is not essential for the survival of blood stage parasites.

Dataset Information

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

Publications

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

Similar Datasets

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