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 viability.

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.

简介：糖原合酶激酶 3-β (GSK-3β) 与神经元细胞变性有关，是治疗阿尔茨海默病 (AD) 的一个有希望的靶点。

方法：在这项工作中，我们通过评估现有 GSK-3β 抑制剂的 IC50 值、推导药效团模型、分子对接模拟、ADME/Tox 特性预测、分子修饰和合成活力预测，对现有 GSK-3β 抑制剂进行了分子建模研究。 .

结果：通过这种方式，抑制剂 15 (CID 57399952) 被选为模板分子，因为它证明具有能够与 GSK-3β 相互作用的相关结构基团，并且除诱变性外还具有良好的 ADME/Tox 预测特性。基于这种抑制剂的化学结构，我们提出了六种类似物，它们对大鼠和小鼠都没有诱变和致癌活性的警报；同样，它们都对抑制 hERG 和合成活力的中等预测提出了低风险警报。

结论：得出的结论是，GSK-3β 抑制剂的类似物在模板分子的毒性终点方面进行了优化，因此被认为是治疗 AD 的新型且有前景的候选药物。