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Exploring the Water-Binding Pocket of the Type II Dehydroquinase Enzyme in the Structure-Based Design of Inhibitors

Lookup NU author(s): Paul Thompson, Professor Alastair Hawkins


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Structural and computational studies to explore the WAT1 binding pocket in the structure-based design of inhibitors against the type 11 dehydroquinase (DHQ2) enzyme are reported. The crystal structures of DHQ2 from M. tuberculosis in complex with four of the reported compounds are described. The electrostatic interaction observed between the guanidinium group of the essential arginine and the carboxylate group of one of the inhibitors in the reported crystal structures supports the recently suggested role of this arginine as the residue that triggers the release of the product from the active site. The results of the structural and molecular dynamics simulation studies revealed that the inhibitory potency is favored by promoting interactions with WAT1 and the residues located within this pocket and, more importantly, by avoiding situations where the ligands occupy the WAT1 binding pocket. The new insights can be used to advantage in the structure-based design of inhibitors.

Publication metadata

Author(s): Blanco B, Sedes A, Peon A, Otero JM, van Raaij MJ, Thompson P, Hawkins AR, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2014

Volume: 57

Issue: 8

Pages: 3494-3510

Print publication date: 24/04/2014

Online publication date: 01/04/2014

Acceptance date: 01/02/2014

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm500175z


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Funder referenceFunder name
Xunta de Galicia
Spanish Ministry of Economy and Competitiveness
Spanish Ministry of Education
GRC2013/041Xunta de Galicia
SAF2010-15076Spanish Ministry of Science and Innovation