Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.
IspD
MEP pathway
Plasmodium falciparum
drug discovery
fragment
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
04 03 2022
04 03 2022
Historique:
revised:
14
12
2021
received:
26
10
2021
pubmed:
18
12
2021
medline:
3
5
2022
entrez:
17
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34918860
doi: 10.1002/cmdc.202100679
pmc: PMC9305118
doi:
Substances chimiques
Sugar Phosphates
0
erythritol 4-phosphate
7183-41-7
Erythritol
RA96B954X6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202100679Informations de copyright
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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