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Crystal Structures of Helicobacter pylori Type II Dehydroquinase Inhibitor Complexes: New Directions for Inhibitor Design

Journal of medicinal chemistry, 2006-02, Vol.49 (4), p.1282-1290 [Peer Reviewed Journal]

2006 INIST-CNRS ;ISSN: 0022-2623 ;EISSN: 1520-4804 ;DOI: 10.1021/jm0505361 ;PMID: 16480265 ;CODEN: JMCMAR

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Title:
Crystal Structures of Helicobacter pylori Type II Dehydroquinase Inhibitor Complexes: New Directions for Inhibitor Design
Author: ROBINSON, David A. ; STEWART, Kirsty A. ; PRICE, Nicholas C. ; CHALK, Peter A. ; COGGINS, John R. ; LAPTHORN, Adrian J.
Subjects: Amino Acid Sequence ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Binding Sites ; Biological and medical sciences ; Citric Acid - chemistry ; Citric Acid - pharmacology ; Crystallography, X-Ray ; Drug Design ; Escherichia coli - drug effects ; Escherichia coli - genetics ; General aspects ; Helicobacter pylori ; Helicobacter pylori - enzymology ; Hydro-Lyases - antagonists & inhibitors ; Hydro-Lyases - chemistry ; Kinetics ; Ligands ; Medical sciences ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Mycobacterium tuberculosis - enzymology ; Pharmacology. Drug treatments ; Quinic Acid - analogs & derivatives ; Quinic Acid - chemistry ; Quinic Acid - pharmacology ; Sequence Alignment ; Streptomyces coelicolor - enzymology ; Structure-Activity Relationship ; Tetrazoles - chemistry ; Tetrazoles - pharmacology ; Xanthones - chemistry ; Xanthones - pharmacology
Is Part Of: Journal of medicinal chemistry, 2006-02, Vol.49 (4), p.1282-1290
Description: 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.
Publisher: Washington, DC: American Chemical Society
Language: English
Identifier: ISSN: 0022-2623
EISSN: 1520-4804
DOI: 10.1021/jm0505361
PMID: 16480265
CODEN: JMCMAR
Source: MEDLINE
Alma/SFX Local Collection

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Crystal Structures of Helicobacter pylori Type II Dehydroquinase Inhibitor Complexes: New Directions for Inhibitor Design

2006 INIST-CNRS ;ISSN: 0022-2623 ;EISSN: 1520-4804 ;DOI: 10.1021/jm0505361 ;PMID: 16480265 ;CODEN: JMCMAR

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