Nanomolar Inhibition of Type II Dehydroquinase Based on the Enolate Reaction Mechanism

• Published in: ChemMedChem 2007-01, Vol.2 (1), p.101-112
• Main Authors: Toscano, Miguel D., Payne, Richard J., Chiba, Akira, Kerbarh, Olivier, Abell, Chris
• Format: Article
• Language: English
• Subjects: Alcohols - chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; antibiotics; Binding Sites; Carboxylic Acids - chemistry; dehydroquinase; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Hydro-Lyases - antagonists & inhibitors; inhibitors; Ketones - chemistry; Kinetics; Ligands; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Streptomyces coelicolor - drug effects; Streptomyces coelicolor - enzymology; Structure-Activity Relationship; Thermodynamics
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200600194

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. Targeting the shikimate pathway: the search for new herbicidal and antimicrobial agents. Potent and selective inhibition of type II dehydroquinase was achieved through rational design. The introduction of a single carboxylate group results in a 1000‐fold increase in potency from the parent compound.