Article ID Journal Published Year Pages File Type
443398 Journal of Molecular Graphics and Modelling 2013 8 Pages PDF
Abstract

Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (124 K)Download as PowerPoint slideHighlights► Pharmacophore model was developed by LigandScout using the complex X-ray structure of Pf dihydrooratate dehydrogenase. ► Pharmcophore-based virtual screening was carried out via MOE. ► Initial hits were docked into the binding pocket of the enzyme. ► Finally some interesting molecules were predicted as new, promising and structurally diverse PfDHODH inhibitors.

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Physical Sciences and Engineering Chemistry Physical and Theoretical Chemistry
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