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.

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.

• Authors: Thomas Fischer, Symeon M Koulas, Anastasia S Tsagkarakou, Efthimios Kyriakis, George A Stravodimos, Vassiliki T Skamnaki, Panagiota G V Liggri, Spyros E Zographos, Rainer Riedl, Demetres D Leonidas
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 7 (Apr 03 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30987252 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• glucopyranosylamine
• Glycogen Phosphorylase
• Glucosamine

Topics

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