PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
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
Fischer, T.; Koulas, S.M.; Tsagkarakou, A.S.; Kyriakis, E.; Stravodimos, G.A.; Skamnaki, V.T.; Liggri, P.G.; Zographos, S.E.; Riedl, R.; Leonidas, D.D. 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. Molecules2019, 24, 1322.
Fischer, T.; Koulas, S.M.; Tsagkarakou, A.S.; Kyriakis, E.; Stravodimos, G.A.; Skamnaki, V.T.; Liggri, P.G.; Zographos, S.E.; Riedl, R.; Leonidas, D.D. 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, 24, 1322.
Fischer, T.; Koulas, S.M.; Tsagkarakou, A.S.; Kyriakis, E.; Stravodimos, G.A.; Skamnaki, V.T.; Liggri, P.G.; Zographos, S.E.; Riedl, R.; Leonidas, D.D. 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. Molecules2019, 24, 1322.
Fischer, T.; Koulas, S.M.; Tsagkarakou, A.S.; Kyriakis, E.; Stravodimos, G.A.; Skamnaki, V.T.; Liggri, P.G.; Zographos, S.E.; Riedl, R.; Leonidas, D.D. 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, 24, 1322.
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.
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.