RT Journal Article
T1 Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies
A1 González Bello, Concepción
K1 Dehydroquinase
K1 Enzyme/inhibitor crystal structures
K1 Essential enzyme motion
K1 Intermediate mimetics
K1 Molecular dynamics simulation studies
K1 Shikimate kinase
K1 Structure-based design
K1 Substrate analogs
AB The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions - cell wall, DNA, RNA, and protein biosynthesis - and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described
PB Bentham Science
SN 1568-0266
YR 2016
FD 2016
LK http://hdl.handle.net/10347/16123
UL http://hdl.handle.net/10347/16123
LA eng
NO González-Bello, C. Curr. Top. Med. Chem. 2016, 16, 960-977
NO Financial support from the Spanish Ministry of Science and Innovation (SAF2013-42899-R), Xunta de Galicia (GRC2013-041) and the European Regional Development Fund (ERDF) is gratefully acknowledged
DS Minerva
RD 23 abr 2026