title: Designing inhibitors against fructose 1,6-bisphosphatase: exploring natural products for novel inhibitor scaffolds.
abstract: Natural products often contain unusual scaffold structures that may be elaborated by combinatorial methods to develop new drug-like molecules. Visual inspection of more than 128 natural products with some type of anti-diabetic activity suggested that a subset might provide novel scaffolds for designing potent inhibitors against fructose 1,6-bisphosphatase (FBPase), an enzyme critical in the control of gluconeogenesis. Using in silico docking methodology, these were evaluated to determine those that exhibited affinity for the AMP binding site. Achyrofuran from the South American plant Achyrocline satureoides, was selected for further investigation. Using the achyrofuran scaffold, inhibitors against FBPase were developed. Compounds 15 and 16 inhibited human liver and pig kidney FBPases at IC50 values comparable to that of AMP, the natural allosteric inhibitor.
authors.affiliation: Department of Chemistry, Boston College, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Heng
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Harris
authors.forename: Evan R
authors.initials: ER
authors.lastname: Kantrowitz
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D006597:Fructose-Bisphosphatase