Design of fructose-2,6-bisphosphatase inhibitors: a novel virtual screening approach.
Fructose-2,6-bisphosphatase (FBPase-2) is a switch between gluconeogenesis and glycolysis in the hepatic cells. The structural features required for inhibitory activity of FBPase-2 were unidentified; no leads are available for inhibiting this important enzyme. In this paper pharmacophore mapping, molecular docking methods were employed in a virtual screening strategy to identify leads for FBPase-2. A receptor based pharmacophore map was modeled which comprised of important interactions as observed in co-crystal of rat liver isozyme with the product inhibitor fructose-6-phosphate. The pharmacophore model was validated against two databases of best docked structural analogues of fructose-2,6-bisphosphate and fructose-6-phosphate. The query generated was submitted for flexible search of ligands in chemical databases, namely LeadQuest, Maybridge and NCI. The hits obtained were further screened by molecular docking using FlexX.
Shaikh
M S
MS
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Mohali, Punjab 160062, India.
Mittal
Amit
A
Bharatam
P V
PV
D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D025481:Phosphofructokinase-2