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Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class
Author(s) -
Diamanti Eleonora,
Hamed Mostafa M.,
Lacour Antoine,
Bravo Patricia,
Illarionov Boris,
Fischer Markus,
Rottmann Matthias,
Witschel Matthias,
Hirsch Anna K. H.
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100679
Subject(s) - fragment (logic) , identification (biology) , enzyme , class (philosophy) , computational biology , chemistry , stereochemistry , biochemistry , biology , computer science , artificial intelligence , algorithm , botany
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, Pf IspD. A systematic SAR investigation afforded a novel chemical structure with a balanced activity–stability profile ( 16 ). Using a homology model of Pf IspD, we proposed a putative binding mode for our newly identified inhibitors that sets the stage for structure‐guided optimization.