High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl- N-acyl-β-d-Glucopyranosylamines as Glycogen Phosphorylase Inhibitors

Molecules. 2019 Apr 3;24(7):1322. doi: 10.3390/molecules24071322.

Abstract

Structure-based design and synthesis of two biphenyl-N-acyl-β-d-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico-derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.

Keywords: N-acyl-β-d-glucopyranosylamine; X-ray crystallography; glycogen metabolism; glycogen phosphorylase inhibitor; structure-based design; type 2 diabetes.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Glucosamine / analogs & derivatives*
  • Glucosamine / chemical synthesis
  • Glucosamine / chemistry
  • Glucosamine / pharmacology
  • Glycogen Phosphorylase / antagonists & inhibitors
  • Glycogen Phosphorylase / chemistry*
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Protein Binding
  • Quantitative Structure-Activity Relationship*

Substances

  • Enzyme Inhibitors
  • glucopyranosylamine
  • Glycogen Phosphorylase
  • Glucosamine