Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases.

摘要: Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, family bis-indoles isolated from various natural sources, are potent kinases, including GSK-3. Using the cocrystal structures indirubins with GSK-3beta, CDK2 CDK5/p25, we modeled binding within ATP-binding pocket these kinases. This modeling approach provided some insight into molecular basis indirubins' action selectivity allowed us to forecast improvements this kinase inhibitors. Predicted molecules, 6-substituted 5,6-disubstituted indirubins, were synthesized evaluated CDK GSK-3 Control, kinase-inactive obtained by introduction methyl substitution on N1.