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.
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
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
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