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

Kyra-Melinda Alexacou, Alia-Cristina Tenchiu Deleanu, Evangelia D Chrysina, Maria-Despoina Charavgi, Ioannis D Kostas, Spyros E Zographos, Nikos G Oikonomakos, Demetres D Leonidas, Kyra-Melinda Alexacou, Alia-Cristina Tenchiu (Deleanu), Evangelia D. Chrysina, Maria-Despoina Charavgi, Ioannis D. Kostas, Spyros E. Zographos, Nikos G. Oikonomakos, Demetres D. Leonidas

Index: Bioorg. Med. Chem. 18(22) , 7911-22, (2010)

Full Text: HTML

Abstract

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-(β-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 α-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3μM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23Å 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 α-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 NO(2), F, Cl, Br, OH, OMe, CF(3), 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 β-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 β-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.Copyright © 2010 Elsevier Ltd. All rights reserved.