Crystal structures of Helicobacter pylori type II dehydroquinase inhibitor complexes: new directions for inhibitor design

Robinson, D.A.,, Stewart, K.A., Price, N.C., Chalk, P.A., Coggins, J.R. and Lapthorn, A.J. (2006) Crystal structures of Helicobacter pylori type II dehydroquinase inhibitor complexes: new directions for inhibitor design. Journal of Medicinal Chemistry, 49(4), pp. 1282-1290. (doi: 10.1021/jm0505361)

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Abstract

The crystal structures of the type II dehydroquinase (DHQase) from Helicobacter pylori in complex with three competitive inhibitors have been determined. The inhibitors are the substrate analogue 2,3-anhydroquinate (FA1), citrate, and an oxoxanthene sulfonamide derivative (AH9095). Despite the very different chemical nature of the inhibitors, in each case the primary point of interaction with the enzyme is via the residues that bind the C1 functionalities of the substrate, 3-dehydroquinate, i.e., N76, H102, I103, and H104. The DHQase/AH9095 complex crystal structure shows that sulfonamides can form a scaffold for nonsubstrate-like inhibitors and identifies a large conserved hydrophobic patch at the entrance to the active site as a locus that can be exploited in the development of new ligands.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lapthorn, Dr Adrian and Price, Prof Nicholas and Coggins, Professor John
Authors: Robinson, D.A.,, Stewart, K.A., Price, N.C., Chalk, P.A., Coggins, J.R., and Lapthorn, A.J.
Subjects:Q Science > QD Chemistry
College/School:College of Science and Engineering > School of Chemistry
College of Medical Veterinary and Life Sciences
Journal Name:Journal of Medicinal Chemistry
ISSN:0022-2623
Published Online:02 February 2006

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