title: Correlation of LUMO localization with the alpha-amylase inhibition constant in a Tendamistat-based series of linear and cyclic peptides.
abstract: The glycosidase alpha-amylase is responsible for the hydrolysis of alpha(1-->4) glycosidic linkages found in dietary starch as one means for controlling blood sugar level. The effect of alpha-amylase is detrimental, however, in the disease state diabetes mellitus, where blood glucose levels are elevated due to a biochemical defect. Inhibition of the enzyme's activity would reduce glucose absorption by the small intestine. Our objective was to develop small peptides based on essential binding elements of the natural protein inhibitor, Tendamistat. These smaller analogs may be better studied structurally and conformationally to help us understand molecular-level interactions. In addition, we have been able to correlate the activity of our compounds with the lowest unoccupied molecular orbital (LUMO) localization in energy-minimized conformations. The positive charge/LUMO of most active inhibitors is localized on the central Arg residue of the required triplet. This provides a predictive model for the design of active molecules.
authors.affiliation: Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA. debbie.heyl-clegg@emich.edu
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Heyl
authors.forename: Steve
authors.initials: S
authors.lastname: Fernandes
authors.forename: Leena
authors.initials: L
authors.lastname: Khullar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stephens
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blaney
authors.forename: Horacia
authors.initials: H
authors.lastname: Opang-Owusu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stahelin
authors.forename: Todd
authors.initials: T
authors.lastname: Pasko
authors.forename: Jana
authors.initials: J
authors.lastname: Jacobs
authors.forename: Danielle
authors.initials: D
authors.lastname: Bailey
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Maria C
authors.initials: MC
authors.lastname: Milletti
mesh_terms: D000818:Animals; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism*; D011487:Protein Conformation; D013552:Swine; D000516:alpha-Amylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D010456:Peptides, Cyclic; D000516:alpha-Amylases; C030526:tendamistate