RT Journal Article
T1 Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme
A1 Prado, Verónica
A1 Lence Quintana, Emilio José
A1 Maneiro Rey, María
A1 Vázquez Ucha, Juan Carlos
A1 Beceiro Casas, Alejandro
A1 Thompson, Paul
A1 Hawkins, Alastair R.
A1 González Bello, Concepción
AB The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL
PB American Chemical Society
SN 0022-2623
YR 2016
FD 2016
LK http://hdl.handle.net/10347/16934
UL http://hdl.handle.net/10347/16934
LA eng
NO Prado, V., Lence, E., Maneiro, M., Vázquez-Ucha, J., Beceiro, A., & Thompson, P. et al. (2016). Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme. Journal Of Medicinal Chemistry, 59(11), 5471-5487. doi: 10.1021/acs.jmedchem.6b00483
NO Financial support from the Spanish Ministry of Economy and Competiveness (SAF2013-42899-R), Xunta de Galicia (GRC2013-041) and the European Regional Development Fund (ERDF) is gratefully acknowledged. V.P. and M.M. thank the Spanish Ministry of Economy and Competiveness and the Spanish Ministry of Education for their respective FPI and FPU fellowships. E.L. thanks the Xunta de Galicia for his postdoctoral fellowship. J.C.V.-U. and A.B. thank the Miguel Servet Programme ISCIII-FEDER (CP13/00226) and the ISCIII General Subdirection of Assesment and Promotion of the Research (PI14/00059) for financial support
DS Minerva
RD 24 abr 2026