Portraying the selectivity of GSK-3 inhibitors towards CDK-2 by 3D similarity and molecular docking

The striking structural resemblance between adenosine triphosphate (ATP) binding sites of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-2 (CDK-2) raises numerous off-target selectivity problems in lead-identification processes that may jeopardize their progress into safe and effective drugs. The structural disparities between GSK-3 and CDK-2 in terms of inhibitors chemical space and binding site characteristics were investigated computationally by ligand-based (3D-similarity search) and structure-based (molecular docking) methods to reproduce the selectivity trend of indirubin derivatives. We attempted to assess distinctive key selectivity features of GSK-3 over CDK-2 with focus on indirubins and to provide a cascade virtual screening approach capable to identify suitable de novo GSK-3 selective scaffolds. Seven inhibitors with higher predicted interaction energies against GSK-3 compared to the highly active reference inhibitor were proposed. Concerted effects between 3D similarity search and docking afforded an exhaustive characterization of the binding site interactions. In spite of inherent challenges and limitations, the workflow developed hereby can be applied to other GSK-3 inhibitors, which display similar inhibitory profile against CDK-2, to rationally design potentially selective scaffolds.