3NC4

The binding of beta-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: a new class of inhibitors

Summary for 3NC4

• Entry DOI: 10.2210/pdb3nc4/pdb
• Descriptor: Glycogen phosphorylase, muscle form, N-({(2E)-2-[(2-hydroxyphenyl)methylidene]hydrazino}carbonothioyl)-beta-D-glucopyranosylamine (3 entities in total)
• Functional Keywords: glycogenolysis, type 2 diabetes, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Total number of polymer chains: 1
• Total formula weight: 98147.01

Authors

Alexacou, K.-M. (deposition date: 2010-06-04, release date: 2011-01-05, Last modification date: 2023-11-22)

Primary citation

Alexacou, K.M.,Tenchiu Deleanu, A.C.,Chrysina, E.D.,Charavgi, M.D.,Kostas, I.D.,Zographos, S.E.,Oikonomakos, N.G.,Leonidas, D.D.
The binding of beta-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: a new class of inhibitors
Bioorg.Med.Chem., 18:7911-7922, 2010

PubMed 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.

PubMed: 20947361
DOI: 10.1016/j.bmc.2010.09.039

Experimental method

X-RAY DIFFRACTION (2.07 Å)