Structure-based design, synthesis, and biological evaluation of non-acyl sulfamate inhibitors of the adenylate-forming enzyme MenE Journal Article
| Authors: | Evans, C. E.; Si, Y.; Matarlo, J. S.; Yin, Y.; French, J. B.; Tonge, P. J.; Tan, D. S. |
| Article Title: | Structure-based design, synthesis, and biological evaluation of non-acyl sulfamate inhibitors of the adenylate-forming enzyme MenE |
| 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. Copyright © 2019 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; nonhuman; protein binding; biosynthesis; protein purification; protein synthesis; escherichia coli; clinical evaluation; crystal structure; binding energy; protein structure; molecular docking; x ray crystallography; biochemistry; mutagenesis; enzymes; adenosine phosphate; isothermal titration calorimetry; biological process; biological evaluation; long chain fatty acid coenzyme a ligase; menaquinone; protein mene; priority journal; article; cell permeability; ic50; cocrystal structure; computational dockings; computational predictions; pharmacokinetic profiles; structure-based designs; n acyl sulfamoyladenosine |
| Journal Title: | Biochemistry |
| Volume: | 58 |
| Issue: | 14 |
| ISSN: | 0006-2960 |
| Publisher: | American Chemical Society |
| Date Published: | 2019-04-09 |
| Start Page: | 1918 |
| End Page: | 1930 |
| Language: | English |
| DOI: | 10.1021/acs.biochem.9b00003 |
| PUBMED: | 30912442 |
| PROVIDER: | scopus |
| PMCID: | PMC6653581 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
