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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.

  • Fischer T Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland. thomas.fischer@zhaw.ch.
  • Koulas SM Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. sym.koulas@gmail.com.
  • Tsagkarakou AS Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. anastasiatsagk@hotmail.com.
  • Kyriakis E Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. kyriakis.ef@gmail.com.
  • Stravodimos GA Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. stravodimos@windowslive.com.
  • Skamnaki VT Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. vskamnaki@bio.uth.gr.
  • Liggri PGV Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. b_liggri@windowslive.com.
  • Zographos SE Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece. sez@eie.gr.
  • Riedl R Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland. rainer.riedl@zhaw.ch.
  • Leonidas DD Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece. ddleonidas@bio.uth.gr.
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  • 2019-04-17
Published in:
  • Molecules (Basel, Switzerland). - 2019
N-acyl-β-d-glucopyranosylamine
X-ray crystallography
glycogen metabolism
glycogen phosphorylase inhibitor
structure-based design
type 2 diabetes
Binding Sites
Catalytic Domain
Chemistry Techniques, Synthetic
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors
Glucosamine
Glycogen Phosphorylase
Humans
Hydrogen Bonding
Models, Molecular
Protein Binding
Quantitative Structure-Activity Relationship
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/188880
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