RT Journal Article
T1 Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment‐Based Approach and Molecular Dynamics Study
A1 Peón López, Antonio
A1 Robles, Adrián
A1 Blanco Rodríguez, Beatriz
A1 Convertino, Marino
A1 Thompson, Paul
A1 Hawkins, Alastair R.
A1 Caflisch, Amedeo
A1 González Bello, Concepción
K1 Antibiotics
K1 Enzyme motion
K1 Fragment-based
K1 Inhibitors
K1 Molecular dynamics
AB 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
PB Wiley
YR 2017
FD 2017-09-19
LK http://hdl.handle.net/10347/16941
UL http://hdl.handle.net/10347/16941
LA eng
NO 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
NO 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
NO Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Numbers: SAF2013-42899-R, SAF2016-75638-RConsellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: ED431G/09European Regional Development FundMinisterio de Educación, Cultura y Deporte
DS Minerva
RD 24 abr 2026