Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2021 Dec 17

PMID 34918860

Citations 5

Authors

Eleonora Diamanti

Mostafa M Hamed

Antoine Lacour

Patricia Bravo

Boris Illarionov

Markus Fischer

Matthias Rottmann

Matthias Witschel

Anna K H Hirsch

Affiliations

Soon will be listed here.

Abstract

The enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the 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.

Citing Articles

Targeting IspD for Anti-infective and Herbicide Development: Exploring Its Role, Mechanism, and Structural Insights.

Willocx D, Diamanti E, Hirsch A J Med Chem. 2025; 68(2):886-901.

PMID: 39749898 PMC: 11770629. DOI: 10.1021/acs.jmedchem.4c01146.

Fragment Discovery by X-Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas Aeruginosa IspD.

Willocx D, DAuria L, Walsh D, Scherer H, Alhayek A, Hamed M Angew Chem Int Ed Engl. 2024; 64(6):e202414615.

PMID: 39676054 PMC: 11796317. DOI: 10.1002/anie.202414615.

Targeting IspD in the Methyl-d-erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity.

Willocx D, Bizzarri L, Alhayek A, Kannan D, Bravo P, Illarionov B J Med Chem. 2024; 67(19):17070-17086.

PMID: 39303294 PMC: 11472328. DOI: 10.1021/acs.jmedchem.4c00212.

New insights into apicoplast metabolism in blood-stage malaria parasites.

Elahi R, Prigge S Curr Opin Microbiol. 2022; 71:102255.

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Comparative genomics of drug-resistant strains of Mycobacterium tuberculosis in Ecuador.

Morey-Leon G, Andrade-Molina D, Fernandez-Cadena J, Berna L BMC Genomics. 2022; 23(1):844.

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