DOCKING STUDIES ON IMIDAZOLIDINE ANALOGUES FOR MANAGEMENT OF DIABETES

Abstract

Glycogen synthase kinase-3I² (GSK-3I²) has recently emerged, in the field of medicinal chemistry, as one of the most attractive therapeutic targets for type II diabetes. Phenylmethylene hydantoins (PMHs) forms strong interactions with the hinge region of GSK-3I²; carbonyl oxygen at position 2 form a H-bonding with backbone nitrogen of Val135 and the NH at position 3 to the carbonyl oxygen of Asp133. The hydantoin ring was sandwiched between Ala83, on top, and Leu188, on the bottom. The aromatic ring is rotated out of plane from the hydantoin plane, allowing extensive interactions with the nucleotide-binding loop. Furthermore, the substituted benzylidene ring system builds an H-bonding interaction with the guanidine moiety of Arg141. Targeting Arg141 is important to improve the activity in the process of designing new derivatives because it is considered the selectivity residue for GSK-3I².