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- Title
Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.
- Authors
Khattri, Ram B.; Morris, Daniel L.; Bilinovich, Stephanie M.; Manandhar, Erendra; Napper, Kahlilah R.; Sweet, Jacob W.; Modarelli, David A.; Leeper, Thomas C.; Stockman, Brian J.
- Abstract
Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable.
- Subjects
ACRYLAMIDE; CYSTEINE; WARHEADS; NUCLEAR magnetic resonance; MOLECULES; CHIMERIC proteins; PROTEIN structure; GLUTAREDOXIN
- Publication
Molecules, 2020, Vol 25, Issue 1, p147
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25010147