Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease
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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Tabriz University of Medical Sciences
2023-11-01
|
| Series: | Advanced Pharmaceutical Bulletin |
| Subjects: | |
| Online Access: | https://apb.tbzmed.ac.ir/PDF/apb-13-688.pdf |
| _version_ | 1797377258906714112 |
|---|---|
| author | Suggala Ramya Shri Suman Manandhar Yogendra Nayak K Sreedhara Ranganath Pai |
| author_facet | Suggala Ramya Shri Suman Manandhar Yogendra Nayak K Sreedhara Ranganath Pai |
| author_sort | Suggala Ramya Shri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T19:50:10Z |
| format | Article |
| id | doaj.art-45825299790844659104d13b4fae9c28 |
| institution | Directory Open Access Journal |
| issn | 2228-5881 2251-7308 |
| language | English |
| last_indexed | 2024-03-08T19:50:10Z |
| publishDate | 2023-11-01 |
| publisher | Tabriz University of Medical Sciences |
| record_format | Article |
| series | Advanced Pharmaceutical Bulletin |
| spelling | doaj.art-45825299790844659104d13b4fae9c282023-12-24T09:28:26ZengTabriz University of Medical SciencesAdvanced Pharmaceutical Bulletin2228-58812251-73082023-11-0113468870010.34172/apb.2023.071apb-39094Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s DiseaseSuggala Ramya Shri0Suman Manandhar1Yogendra Nayak2K Sreedhara Ranganath Pai3Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal -576104, India.Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal -576104, India.Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal -576104, India.Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal -576104, India.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.https://apb.tbzmed.ac.ir/PDF/apb-13-688.pdfalzheimer’s diseaseallosteric inhibitorsglycogen synthase kinase-3betaatp-competitive inhibitorsproinflammatory cytokinesgsk-3β drug binding pockets |
| spellingShingle | Suggala Ramya Shri Suman Manandhar Yogendra Nayak K Sreedhara Ranganath Pai Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease Advanced Pharmaceutical Bulletin alzheimer’s disease allosteric inhibitors glycogen synthase kinase-3beta atp-competitive inhibitors proinflammatory cytokines gsk-3β drug binding pockets |
| title | Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease |
| title_full | Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease |
| title_fullStr | Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease |
| title_full_unstemmed | Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease |
| title_short | Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease |
| title_sort | role of gsk 3β inhibitors new promises and opportunities for alzheimer s disease |
| topic | alzheimer’s disease allosteric inhibitors glycogen synthase kinase-3beta atp-competitive inhibitors proinflammatory cytokines gsk-3β drug binding pockets |
| url | https://apb.tbzmed.ac.ir/PDF/apb-13-688.pdf |
| work_keys_str_mv | AT suggalaramyashri roleofgsk3binhibitorsnewpromisesandopportunitiesforalzheimersdisease AT sumanmanandhar roleofgsk3binhibitorsnewpromisesandopportunitiesforalzheimersdisease AT yogendranayak roleofgsk3binhibitorsnewpromisesandopportunitiesforalzheimersdisease AT ksreedhararanganathpai roleofgsk3binhibitorsnewpromisesandopportunitiesforalzheimersdisease |