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dc.contributor.authorPeón López, Antonio
dc.contributor.authorRobles, Adrián
dc.contributor.authorBlanco Rodríguez, Beatriz
dc.contributor.authorConvertino, Marino
dc.contributor.authorThompson, Paul
dc.contributor.authorHawkins, Alastair R.
dc.contributor.authorCaflisch, Amedeo
dc.contributor.authorGonzález Bello, Concepción
dc.date.accessioned2018-07-03T12:42:53Z
dc.date.available2018-09-12T01:00:09Z
dc.date.issued2017-09-19
dc.identifier.citationPeón, A., Robles, A., Blanco, B., Convertino, M., Thompson, P., & Hawkins, A. et al. (2017). Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Chemmedchem, 12(18), 1512-1524. doi: 10.1002/cmdc.201700396
dc.identifier.urihttp://hdl.handle.net/10347/16941
dc.descriptionThis is the peer-reviewed version of the following article: Peón, A., Robles, A., Blanco, B., Convertino, M., Thompson, P., & Hawkins, A. et al. (2017). Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Chemmedchem, 12(18), 1512-1524, which has been published in final form at https://doi.org/10.1002/cmdc.201700396. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving
dc.description.abstractA multidisciplinary approach was used to identify and optimize a quinazolinedione‐based ligand that would decrease the flexibility of the substrate‐covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer‐aided fragment‐based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance. Chemical modification of its non‐aromatic moiety through an olefin cross‐metathesis and Seebach's self‐reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme′s catalytic cycle. Molecular dynamics simulations revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active site
dc.description.sponsorshipSecretaría de Estado de Investigación, Desarrollo e Innovación. Grant Numbers: SAF2013-42899-R, SAF2016-75638-R Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: ED431G/09 European Regional Development Fund Ministerio de Educación, Cultura y Deporte
dc.language.isoeng
dc.publisherWiley
dc.rights© 2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving
dc.subjectAntibiotics
dc.subjectEnzyme motion
dc.subjectFragment-based
dc.subjectInhibitors
dc.subjectMolecular dynamics
dc.titleReducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment‐Based Approach and Molecular Dynamics Study
dc.typejournal article
dc.identifier.doi10.1002/cmdc.201700396
dc.relation.publisherversionhttps://doi.org/10.1002/cmdc.201700396
dc.type.hasVersionAM
dc.identifier.essn1860-7187
dc.rights.accessRightsopen access
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-42899-R/ES/DESARROLLO DE NUEVOS ANTIBIOTICOS PARA EL TRATAMIENTO DE INFECCIONES BACTERIANAS RESISTENTES: METABOLISMO, RESISTENCIA Y COMUNICACION CELULA-CELULA
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75638-R/ES


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