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Article

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

by
Thomas Fischer
1,†,
Symeon M. Koulas
2,†,
Anastasia S. Tsagkarakou
2,†,
Efthimios Kyriakis
2,
George A. Stravodimos
2,
Vassiliki T. Skamnaki
2,
Panagiota G.V. Liggri
2,3,
Spyros E. Zographos
3,
Rainer Riedl
1,* and
Demetres D. Leonidas
2,*
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
Submission 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.
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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MDPI and ACS Style

Fischer, T.; Koulas, S.M.; Tsagkarakou, A.S.; Kyriakis, E.; Stravodimos, G.A.; Skamnaki, V.T.; Liggri, P.G.V.; 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. https://doi.org/10.3390/molecules24071322

AMA Style

Fischer T, Koulas SM, Tsagkarakou AS, Kyriakis E, Stravodimos GA, Skamnaki VT, Liggri PGV, Zographos SE, Riedl R, Leonidas DD. 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(7):1322. https://doi.org/10.3390/molecules24071322

Chicago/Turabian Style

Fischer, Thomas, Symeon M. Koulas, Anastasia S. Tsagkarakou, Efthimios Kyriakis, George A. Stravodimos, Vassiliki T. Skamnaki, Panagiota G.V. Liggri, Spyros E. Zographos, Rainer Riedl, and Demetres D. Leonidas. 2019. "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 24, no. 7: 1322. https://doi.org/10.3390/molecules24071322

APA Style

Fischer, T., Koulas, S. M., Tsagkarakou, A. S., Kyriakis, E., Stravodimos, G. A., Skamnaki, V. T., Liggri, P. G. V., Zographos, S. E., Riedl, R., & Leonidas, D. D. (2019). 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, 24(7), 1322. https://doi.org/10.3390/molecules24071322

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