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Targeting the IspD enzyme in the MEP pathway: identification of a novel fragment class

Hirsch, A. K. H. and Diamanti, E. and Hamed, M. M. and Lacour, A. and Bravo, P. and Illarionov, B. and Fischer, M. and Rottmann, M. and Witschel, M.. (2022) Targeting the IspD enzyme in the MEP pathway: identification of a novel fragment class. ChemMedChem, 17. e202100679.

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Abstract

Enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate 2C-methyl-D-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the huge large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high-throughput screening approach that led to the discovery of a novel fragment hit active against the third enzyme of the MEP pathway, PfIspD. A systematic SAR investigation afforded a novel chemical structure with a balanced activity-stability profile (16). Using a homology model of PfIspD, we proposed a putative binding mode for our newly identified inhibitors that sets the stage for structure-guided optimization.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias and Bravo, Patricia
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1860-7187 (Electronic)1860-7179 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:27 Dec 2022 10:07
Deposited On:27 Dec 2022 10:07

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