Nanomolar inhibition of type II dehydroquinase based on the enolate reaction mechanism.
We describe the rational design of a novel, highly potent inhibitor of type II dehydroquinase, the dicarboxylate 6. The incorporation of a carboxylate at the 3-position mimics the putative enolate intermediate in the reaction mechanism, and allows a potential electrostatic binding interaction with the arginine on the active site flap. This results in a 1000-fold increase in potency, making the dicarboxylate 6 the most potent inhibitor of type II dehydroquinase reported to date, with a high ligand efficiency of -0.68 kcal mol(-1) per nonhydrogen atom. The systematic dissection of 6 in compounds 7-12, all of which show a drop in potency, confirm the synergistic importance of the two carboxylates, the C3 and C4 hydroxyl groups, and the anhydroquinate ring structure for the potency of 6.
Toscano
Miguel D
MD
Department of Chemistry, University of Cambridge, University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK.
Payne
Richard J
RJ
Chiba
Akira
A
Kerbarh
Olivier
O
Abell
Chris
C
D000438:Alcohols / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D048372:Streptomyces coelicolor / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000438:Alcohols; D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007659:Ketones; D008024:Ligands; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase