Journal
BIOCHEMISTRY
Volume 58, Issue 14, Pages 1918-1930Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.9b00003
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [R01 GM100477, R01 GM102864, R35 GM124898, T32 GM073546, P30 CA008748]
- W. Burghardt Turner Fellowship
- National Institutes of Health [GM0080]
- U.S. Department of Energy [DE-AC02-98CH10886]
Ask authors/readers for more resources
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 (IC50 = 8 mu M; 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available