Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 13 4 2023 11 01 Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease 688 700 10.34172/apb.2023.071 EN Suggala Ramya Shri https://orcid.org/0000-0001-5527-4496 Suman Manandhar https://orcid.org/0000-0002-6562-4047 Yogendra Nayak https://orcid.org/0000-0002-0508-1394 K Sreedhara Ranganath Pai https://orcid.org/0000-0002-2017-9533 REVIEW 10.34172/apb.2023.071 2022 07 08 2023 01 20 Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signaling pathways. Dysregulation of GSK-3β kinase has been reported in diabetes, cancer, Alzheimer’s disease, schizophrenia, bipolar disorder, inflammation, and Huntington’s disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer’s disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produce disarrangement of the cytoskeleton, neurofibrillary tangles formation, and lead to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3β inhibitors and discussed their futuristic opportunities as anti-Alzheimer’s compounds.