High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-<i>N</i>-acyl-β-<span style="font-variant: small-caps">d</span>-Glucopyranosylamines as Glycogen Phosphorylase Inhibitors
oleh: 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
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2019-04-01 |
Deskripsi
Structure-based design and synthesis of two biphenyl-<i>N</i>-acyl-β-<span style="font-variant: small-caps;">d</span>-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.