Preprint Article Version 1 This version is not peer-reviewed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

Version 1 : Received: 15 March 2019 / Approved: 15 March 2019 / Online: 15 March 2019 (14:06:06 CET)

A peer-reviewed article of this Preprint also exists.

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. Molecules 2019, 24, 1322.

Journal reference: Molecules 2019, 24, 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.

Subject Areas

Structure-based design; glycogen phosphorylase inhibitor; glycogen metabolism; type 2 diabetes; X-ray crystallography; N-acyl-β-D-glucopyranosylamine

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