Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE

Christopher E. Evans, Yuanyuan Si, Joe S. Matarlo, Yue Yin, Jarrod B. French, Peter J. Tonge, Derek S. Tan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC 50 = 8 μM; K d = 244 nM), and its X-ray co-crystal structure was determined to characterize its binding mode in comparison to the computational prediction. This work provides a framework for the development of potent non-acyl sulfamate inhibitors of other adenylate-forming enzymes in the future.

Original languageEnglish (US)
Pages (from-to)1918-1930
Number of pages13
JournalBiochemistry
Volume58
Issue number14
DOIs
StatePublished - Apr 9 2019
Externally publishedYes

Bibliographical note

Funding Information:
#C.E.E. and Y.S. contributed equally to this work. Funding This work was supported by the National Institutes of Health (NIH) (R01 GM100477 to D.S.T., R01 GM102864 to P.J.T., R35 GM124898 to J.B.F., T32 GM073546-Gross to C.E.E., and Cancer Center Support Grant P30 CA008748 to C. B. Thompson) and a W. Burghardt Turner Fellowship (to J.S.M.). The National Synchrotron Light Source is supported by National Institutes of Health Grant GM0080 (supplement to a PSI program) and U.S. Department of Energy Contract DE-AC02-98CH10886.

Publisher Copyright:
Copyright © 2019 American Chemical Society.

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