Lookup NU author(s): Paul Thompson,
Professor Alastair Hawkins
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Shikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5-aminoshikimic acid and the natural substrate enhances the selectivity for the H. pylori enzyme due to key motion differences in the shikimic acid binding domain (mainly helix alpha 5). These studies show that the less-exploited motion-based design approach not only is an alternative strategy for the development of competitive inhibitors, but could also be a way to achieve selectivity against a particular enzyme among its homologues.
Author(s): Prado V, Lence E, Thompson P, Hawkins AR, Gonzalez-Bello C
Publication type: Article
Publication status: Published
Journal: Chemistry A European Journal
Print publication date: 12/12/2016
Online publication date: 04/10/2016
Acceptance date: 01/01/1900
ISSN (print): 0947-6539
ISSN (electronic): 1521-3765
Publisher: Wiley-Blackwell Publishing, Inc.
Altmetrics provided by Altmetric