Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach
Abstract Significant implications of glycogen synthase kinase-3β (GSK-3β) have been reported in various neuronal disorders and malignant cancers. GSK-3β modulates diverse protein targets through phosphorylation, and its aberrant activity leads to neurological complications as well as tumour onset. T...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-85868-5 |
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| author | Shabir Ahmad Ganai Suma Mohan Shahid Ahmad Padder |
| author_facet | Shabir Ahmad Ganai Suma Mohan Shahid Ahmad Padder |
| author_sort | Shabir Ahmad Ganai |
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| description | Abstract Significant implications of glycogen synthase kinase-3β (GSK-3β) have been reported in various neuronal disorders and malignant cancers. GSK-3β modulates diverse protein targets through phosphorylation, and its aberrant activity leads to neurological complications as well as tumour onset. Therefore, inhibiting GSK-3β activity through active-site fitting molecules may offer a favourable strategy for intercepting these disorders. This comprehensive study used multiple assays in tandem in order to explore the most potent GSK-3β inhibitor. Following structural similarity screening, 135 molecular docking and 135 standard MM-GBSA experiments were performed using AZD1080, a known inhibitor as standard. Among the 32 molecules demonstrating a stronger binding affinity than reference, only the two most potent molecules were chosen and their binding free energy was compared to AZD1080 using the Desmond trajectory clustering and eventual MM-GBSA. Additionally, the interaction status of these molecules and AZD1080 with GSK-3β was explored post-molecular dynamics. The stability of the strongest molecule (most potent) was evaluated in the active site of the above-mentioned kinase keeping its apo-form as reference. Notably, the e-Pharmacophores mapping was performed to address the level of complementarity of the most potent molecule and AZD1080 with the functional site of GSK-3β. Using various techniques, we identified the molecule with PubChem CID: 11167509 as the strongest molecule for obstructing GSK-3β, which may serve as a promising therapeutic after the meticulous evaluation on diverse models. |
| format | Article |
| id | doaj-art-aa31ae24f07f4c0d8b81fb45e621b37a |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-aa31ae24f07f4c0d8b81fb45e621b37a2025-02-09T12:35:23ZengNature PortfolioScientific Reports2045-23222025-02-0115111610.1038/s41598-025-85868-5Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approachShabir Ahmad Ganai0Suma Mohan1Shahid Ahmad Padder2Division of Basic Sciences & Humanities, FoH, SKUAST-Kashmir, ShalimarSchool of Chemical and Biotechnology, SASTRA Deemed to be UniversityDivision of Basic Sciences & Humanities, FoH, SKUAST-Kashmir, ShalimarAbstract Significant implications of glycogen synthase kinase-3β (GSK-3β) have been reported in various neuronal disorders and malignant cancers. GSK-3β modulates diverse protein targets through phosphorylation, and its aberrant activity leads to neurological complications as well as tumour onset. Therefore, inhibiting GSK-3β activity through active-site fitting molecules may offer a favourable strategy for intercepting these disorders. This comprehensive study used multiple assays in tandem in order to explore the most potent GSK-3β inhibitor. Following structural similarity screening, 135 molecular docking and 135 standard MM-GBSA experiments were performed using AZD1080, a known inhibitor as standard. Among the 32 molecules demonstrating a stronger binding affinity than reference, only the two most potent molecules were chosen and their binding free energy was compared to AZD1080 using the Desmond trajectory clustering and eventual MM-GBSA. Additionally, the interaction status of these molecules and AZD1080 with GSK-3β was explored post-molecular dynamics. The stability of the strongest molecule (most potent) was evaluated in the active site of the above-mentioned kinase keeping its apo-form as reference. Notably, the e-Pharmacophores mapping was performed to address the level of complementarity of the most potent molecule and AZD1080 with the functional site of GSK-3β. Using various techniques, we identified the molecule with PubChem CID: 11167509 as the strongest molecule for obstructing GSK-3β, which may serve as a promising therapeutic after the meticulous evaluation on diverse models.https://doi.org/10.1038/s41598-025-85868-5GSK-3βShape based screeningXP-dockingTrajectory clusteringMolecular dynamics simulatione-Pharmacophores modelling |
| spellingShingle | Shabir Ahmad Ganai Suma Mohan Shahid Ahmad Padder Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach Scientific Reports GSK-3β Shape based screening XP-docking Trajectory clustering Molecular dynamics simulation e-Pharmacophores modelling |
| title | Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach |
| title_full | Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach |
| title_fullStr | Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach |
| title_full_unstemmed | Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach |
| title_short | Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach |
| title_sort | exploring novel and potent glycogen synthase kinase 3β inhibitors through systematic drug designing approach |
| topic | GSK-3β Shape based screening XP-docking Trajectory clustering Molecular dynamics simulation e-Pharmacophores modelling |
| url | https://doi.org/10.1038/s41598-025-85868-5 |
| work_keys_str_mv | AT shabirahmadganai exploringnovelandpotentglycogensynthasekinase3binhibitorsthroughsystematicdrugdesigningapproach AT sumamohan exploringnovelandpotentglycogensynthasekinase3binhibitorsthroughsystematicdrugdesigningapproach AT shahidahmadpadder exploringnovelandpotentglycogensynthasekinase3binhibitorsthroughsystematicdrugdesigningapproach |