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Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme

Lookup NU author(s): Paul Thompson, Professor Alastair Hawkins


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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.

Publication metadata

Author(s): Prado V, Lence E, Thompson P, Hawkins AR, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: Chemistry A European Journal

Year: 2016

Volume: 22

Issue: 50

Pages: 17987-17999

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.


DOI: 10.1002/chem.201602923


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Funder referenceFunder name
European Regional Development Fund (ERDF)
Spanish Ministry of Economy and Competiveness
Xunta de Galicia
GRC2013-041Xunta de Galicia
SAF2013-42899-RSpanish Ministry of Economy and Competiveness