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Molecules 2016, 21(7), 846;

An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor

Department of Chemistry and Biochemistry, The University of Akron, Akron, OH 44325, USA
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editors: Raymond S. Norton and Martin J. Scanlon
Received: 29 March 2016 / Revised: 20 June 2016 / Accepted: 22 June 2016 / Published: 16 July 2016
(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)
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Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and 15N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins—a heretofore untapped reservoir for antibiotic agents. View Full-Text
Keywords: glutaredoxin; FBDD; STD; HSQC; trNOE; warhead; ortholog; docking glutaredoxin; FBDD; STD; HSQC; trNOE; warhead; ortholog; docking

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Khattri, R.B.; Morris, D.L.; Davis, C.M.; Bilinovich, S.M.; Caras, A.J.; Panzner, M.J.; Debord, M.A.; Leeper, T.C. An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor. Molecules 2016, 21, 846.

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