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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

1
Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland
2
Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
3
Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(7), 1322; https://doi.org/10.3390/molecules24071322
Received: 15 March 2019 / Revised: 30 March 2019 / Accepted: 1 April 2019 / Published: 3 April 2019
(This article belongs to the Special Issue Drug Design)
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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. View Full-Text
Keywords: structure-based design; glycogen phosphorylase inhibitor; glycogen metabolism; type 2 diabetes; X-ray crystallography; N-acyl-β-d-glucopyranosylamine structure-based design; glycogen phosphorylase inhibitor; glycogen metabolism; type 2 diabetes; X-ray crystallography; N-acyl-β-d-glucopyranosylamine
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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 (CC BY 4.0).

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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.

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