A library of novel allosteric inhibitors against fructose 1,6-bisphosphatase.
The identification of a proper lead compound for fructose 1,6-bisphosphatase (FBPase) is a critical step in the process of developing novel therapeutics against type-2 diabetes. Herein, we have successfully generated a library of allosteric inhibitors against FBPase as potential anti-diabetic drugs, of which, the lead compound 1b was identified through utilizing a virtual high-throughput screening (vHTS) system, which we have developed. The thiazole-based core structure was synthesized via the condensation of alpha-bromo-ketones with thioureas and substituents on the two aryl rings were varied. 4c was found to inhibit pig kidney FBPase approximately fivefold better than 1b. In addition, we have also identified 10b, a tight binding fragment, which can be use for fragment-based drug design purposes.
Heng
Sabrina
S
Boston College, Department of Chemistry, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA.
Gryncel
Kimberly R
KR
Kantrowitz
Evan R
ER
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D013552:Swine
D004791:Enzyme Inhibitors; D006597:Fructose-Bisphosphatase