title: Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme.
abstract: 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 α5). 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.
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain.
authors.forename: Verónica
authors.identifier: http://orcid.org/0000-0002-9812-7944
authors.initials: V
authors.lastname: Prado
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain.
authors.forename: Emilio
authors.identifier: http://orcid.org/0000-0001-9489-9421
authors.initials: E
authors.lastname: Lence
authors.affiliation: Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0002-3365-1980
authors.initials: P
authors.lastname: Thompson
authors.affiliation: Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Hawkins
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain.
authors.forename: Concepción
authors.identifier: http://orcid.org/0000-0001-6439-553X
authors.initials: C
authors.lastname: González-Bello
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005615:Freezing; D016480:Helicobacter pylori / Q000737:chemistry / Q000201:enzymology*; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012765:Shikimic Acid / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C494532:5-amino-5-deoxyshikimic acid; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012765:Shikimic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase
keywords: antibiotics; enzyme catalysis; enzymes; inhibitors; molecular dynamics