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Concepts and Core Principles of Fragment-Based Drug Design
Open AccessArticle

Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead

1
Department of Physiology and Functional genomics, University of Florida, Gainesville, FL 32610, USA
2
Department of Chemistry and Biochemistry, The University of Akron, Akron, OH 44325, USA
3
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA
4
Department of Chemistry, Berea College, Berea, KY 40404, USA
5
Department of Chemistry and Biochemistry, Kennesaw State University, GA 30144, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current Address: Biochemistry and Biophysics Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Academic Editor: Brian J. Stockman
Molecules 2020, 25(1), 147; https://doi.org/10.3390/molecules25010147
Received: 26 November 2019 / Revised: 20 December 2019 / Accepted: 23 December 2019 / Published: 30 December 2019
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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. View Full-Text
Keywords: glutaredoxin; FBDD; STD; HSQC; trNOE; acrylamide warhead; docking; covalent inhibition glutaredoxin; FBDD; STD; HSQC; trNOE; acrylamide warhead; docking; covalent inhibition
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Khattri, R.B.; Morris, D.L.; Bilinovich, S.M.; Manandhar, E.; Napper, K.R.; Sweet, J.W.; Modarelli, D.A.; Leeper, T.C. Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead. Molecules 2020, 25, 147.

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