Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsJumde, Ravindra P
Gierse, Robin M
Elgaher, Walid A M
Neusens, Philipp J
Hirsch, Anna K H
MetadataShow full item record
AbstractTarget-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC to first identify and subsequently optimize binders/inhibitors of the anti-infective target DXPS. The initial hits were also optimized for their antibacterial activity against E. coli and M. tuberculosis during subsequent tdDCC runs. Using tdDCC, we were able to generate acylhydrazone-based inhibitors of DXPS. The tailored tdDCC runs also provided insights into the structure-activity relationship of this novel class of DXPS inhibitors. The competition tdDCC runs provided important information about the mode of inhibition of acylhydrazone-based inhibitors. This approach holds the potential to expedite the drug-discovery process and should be applicable to a range of biological targets.
CitationChem Sci. 2021 Apr 28;12(22):7775-7785. doi: 10.1039/d1sc00330e.
AffiliationHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
PublisherRoyal Society of Chemistry
The following license files are associated with this item:
- Creative Commons
- Conformational dynamics of 1-deoxy-d-xylulose 5-phosphate synthase on ligand binding revealed by H/D exchange MS.
- Authors: Zhou J, Yang L, DeColli A, Freel Meyers C, Nemeria NS, Jordan F
- Issue date: 2017 Aug 29
- X-ray crystallography-based structural elucidation of enzyme-bound intermediates along the 1-deoxy-d-xylulose 5-phosphate synthase reaction coordinate.
- Authors: Chen PY, DeColli AA, Freel Meyers CL, Drennan CL
- Issue date: 2019 Aug 16
- Dynamic Combinatorial Chemistry: A New Methodology Comes of Age.
- Authors: Frei P, Hevey R, Ernst B
- Issue date: 2019 Jan 2
- Mechanistic Studies of 1-Deoxy-D-Xylulose-5-Phosphate Synthase from <i>Deinococcus radiodurans</i>.
- Authors: Handa S, Dempsey DR, Ramamoorthy D, Cook N, Guida WC, Spradling TJ, White JK, Woodcock HL, Merkler DJ
- Issue date: 2018
- Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum.
- Authors: Singh VK, Ghosh I
- Issue date: 2013 Sep 2