Design, synthesis and evaluation of bifunctional inhibitors of type II dehydroquinase.
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.
Toscano
Miguel D
MD
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
Frederickson
Martyn
M
Evans
David P
DP
Coggins
John R
JR
Abell
Chris
C
González-Bello
Concepción
C
D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011801:Quinic Acid / Q000737:chemistry; D012485:Salmonella typhi / Q000201:enzymology; D013302:Streptomyces / Q000201:enzymology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011801:Quinic Acid; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase