High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-<i>N</i>-acyl-β-<span style="font-variant: small-caps">d</span>-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
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.
