title: Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme.
abstract: The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and 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.initials: V
authors.lastname: Prado
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and 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.initials: E
authors.lastname: Lence
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela , calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Maneiro
authors.affiliation: Servicio de Microbioloxía-INIBIC, Complexo Hospitalario Universitario A Coruña (CHUAC) , 15006 A Coruña, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Vázquez-Ucha
authors.affiliation: Servicio de Microbioloxía-INIBIC, Complexo Hospitalario Universitario A Coruña (CHUAC) , 15006 A Coruña, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Beceiro
authors.affiliation: Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne , Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
authors.affiliation: Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne , Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Hawkins
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and 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.initials: C
authors.lastname: González-Bello
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase