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

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

doi:10.3390/molecules24071322

Molecules (Apr 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

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

Affiliations

Thomas Fischer: Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland
Symeon M. Koulas: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Anastasia S. Tsagkarakou: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Efthimios Kyriakis: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
George A. Stravodimos: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Vassiliki T. Skamnaki: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Panagiota G.V. Liggri: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Spyros E. Zographos: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece
Rainer Riedl: Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland
Demetres D. Leonidas: Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece

DOI: https://doi.org/10.3390/molecules24071322
Journal volume & issue: Vol. 24, no. 7
p. 1322

Abstract

Read online

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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

About the journal

Abstract

Keywords