Issue 12, 2003

Design, synthesis and evaluation of bifunctional inhibitors of type II dehydroquinase

Abstract

Inhibitors of type II dehydroquinase were designed to straddle the two distinct binding sites identified for the inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid and a glycerol molecule in a crystallographic study of the Streptomyces coelicolor enzyme. A number of compounds were designed to incorporate characteristics of both ligands. These analogues were synthesized from quinic acid, and were assayed against type I (Salmonella typhi) and type II (S. coelicolor) dehydroquinases. None of the analogues showed inhibition for type I dehydroquinase. Six of the analogues were shown to have inhibition constants in the micromolar to low millimolar range against the S. coelicolor type II dehydroquinase, while two showed no inhibition. The binding modes of the analogues in the active site of the S. coelicolor enzyme were studied by molecular docking with GOLD1.2. These studies suggest a binding mode where the ring is in a similar position to (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid in the crystal structure and the side-chain occupies part of the glycerol binding-pocket.

Graphical abstract: Design, synthesis and evaluation of bifunctional inhibitors of type II dehydroquinase

Supplementary files

Article information

Article type
Paper
Submitted
05 févr. 2003
Accepted
02 mai 2003
First published
15 mai 2003

Org. Biomol. Chem., 2003,1, 2075-2083

Design, synthesis and evaluation of bifunctional inhibitors of type II dehydroquinase

M. D. Toscano, M. Frederickson, D. P. Evans, J. R. Coggins, C. Abell and C. González-Bello, Org. Biomol. Chem., 2003, 1, 2075 DOI: 10.1039/B301731A

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