Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.

Abstract DYRK1A has been associated with Down’s syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC 50  = 130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.