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

✍ Scribed by Miguel D. Toscano; Richard J. Payne; Akira Chiba; Olivier Kerbarh; Chris Abell

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 276 KB
• Volume: 2
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200600194

✦ Synopsis

Abstract

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.