Peón López, AntonioRobles, AdriánBlanco Rodríguez, BeatrizConvertino, MarinoThompson, PaulHawkins, Alastair R.Caflisch, AmedeoGonzález Bello, Concepción2018-07-032018-09-122017-09-19Peón, 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.201700396http://hdl.handle.net/10347/16941This 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-ArchivingA 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 siteeng© 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-ArchivingAntibioticsEnzyme motionFragment-basedInhibitorsMolecular dynamicsjournal article10.1002/cmdc.2017003961860-7187open access