Introduction: The enzyme Glycogen Synthase Kinase 3-β (GSK-3β) is related to neuronal
cell degeneration, representing a promising target to treat Alzheimer’s Disease (AD).
Methods: In this work, we performed a molecular modeling study of existing GSK-3β inhibitors by
means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking
simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic
Results: In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it
demonstrated to bear relevant structural groups able to interact with GSK-3β, and also presented
favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical
structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic
activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition
of hERG and medium prediction of synthetic viability.
Conclusion: It is concluded that the analogues of GSK-3β inhibitors were optimized in relation to
the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising
drug candidates for AD treatment.