IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening.

PloS One
Naomi Tidten-LukschRuth Brenk

Abstract

CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens.

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Citations

Jul 17, 2013·Drug Discovery Today·Tiziana MasiniAnna K H Hirsch
Jan 30, 2015·Angewandte Chemie·Elke PerschFrançois Diederich

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Methods Mentioned

BETA
co-crystallisation

Software Mentioned

Feature Trees
MOLOC
FTrees
DOCK
Sybyl
PyMol PyMOL
GraFit
AMSOL
MySQL

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