Correlation of LUMO localization with the α-amylase inhibition constant in a Tendamistat-based series of linear and cyclic peptides

Deborah L. Heyl, Steve Fernandes, Leena Khullar, Jennifer Stephens, Elizabeth Blaney, Horacia Opang-Owusu, Benjamin Stahelin, Todd Pasko, Jana Jacobs, Danielle Bailey, Dennis Brown, Maria C. Milletti

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The glycosidase α-amylase is responsible for the hydrolysis of α(1→4) glycosidic linkages found in dietary starch as one means for controlling blood sugar level. The effect of α-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.

Original languageEnglish
Pages (from-to)4262-4268
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number13
DOIs
StatePublished - Jul 1 2005

Keywords

  • Inhibitor
  • Peptide
  • Tendamistat
  • α-Amylase

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