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

AnastasiaS. Tsagkarakou¹  GeorgeA. Stravodimos¹  SymeonM. Koulas¹  Efthimios Kyriakis¹  VassilikiT. Skamnaki¹  DemetresD. Leonidas¹  PanagiotaG.V. Liggri¹  SpyrosE. Zographos²  Rainer Riedl³  Thomas Fischer³ 

[1] Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece;Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece;Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland;

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

DOI  :  10.3390/molecules24071322

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown