4.7 Article

The binding of β-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 22, 页码 7911-7922

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.09.039

关键词

Type 2 diabetes; Glycogen phosphorylase; Glucopyranosyl-thiosemicarbazones; Inhibition; X-ray crystallography

资金

  1. EU [MEST-CT-020575]
  2. Commission of the European Communities [CSA-SA_FP7-REGPOT-2008-1, 230146]
  3. European Community

向作者/读者索取更多资源

Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(beta-D-glucopyranosyl) thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to alpha-D-glucose- 1-phosphate with IC50 values ranging from 5.7 to 524.3 mu M. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23 angstrom resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as alpha-D-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO2, F, Cl, Br, OH, OMe, CF3, or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the beta-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the beta-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme. (C) 2010 Elsevier Ltd. All rights reserved.

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