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dc.contributor.author | Peón López, Antonio |
dc.contributor.author | Robles, Adrián |
dc.contributor.author | Blanco Rodríguez, Beatriz |
dc.contributor.author | Convertino, Marino |
dc.contributor.author | Thompson, Paul |
dc.contributor.author | Hawkins, Alastair R. |
dc.contributor.author | Caflisch, Amedeo |
dc.contributor.author | González Bello, Concepción |
dc.date.accessioned | 2018-07-03T12:42:53Z |
dc.date.available | 2018-09-12T01:00:09Z |
dc.date.issued | 2017-09-19 |
dc.identifier.citation | 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. doi: 10.1002/cmdc.201700396 |
dc.identifier.uri | http://hdl.handle.net/10347/16941 |
dc.description | This 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.abstract | A 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.sponsorship | Secretaría 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.iso | eng |
dc.publisher | Wiley |
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.subject | Antibiotics |
dc.subject | Enzyme motion |
dc.subject | Fragment-based |
dc.subject | Inhibitors |
dc.subject | Molecular dynamics |
dc.title | Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment‐Based Approach and Molecular Dynamics Study |
dc.type | journal article |
dc.identifier.doi | 10.1002/cmdc.201700396 |
dc.relation.publisherversion | https://doi.org/10.1002/cmdc.201700396 |
dc.type.hasVersion | AM |
dc.identifier.essn | 1860-7187 |
dc.rights.accessRights | open access |
dc.contributor.affiliation | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares |
dc.contributor.affiliation | Universidade de Santiago de Compostela. Departamento de Química Orgánica |
dc.description.peerreviewed | SI |
dc.relation.projectID | info: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.projectID | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75638-R/ES |
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