Screening of Azadirachta indica phytoconstituents as GSK-3β inhibitor and its 
implication in neuroblastoma: molecular docking, molecular dynamics, MM-PBSA 
binding energy, and in-vitro study

Chandel, S; Singh, R; Gautam, A; Ravichandiran, V

doi:10.1080/07391102.2021.1977705

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Screening of Azadirachta indica phytoconstituents as GSK-3β inhibitor and its implication in neuroblastoma: molecular docking, molecular dynamics, MM-PBSA binding energy, and in-vitro study

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Gautam, A
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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引用

Chandel, S., Singh, R., Gautam, A., & Ravichandiran, V. (2021). Screening of Azadirachta indica phytoconstituents as GSK-3β inhibitor and its implication in neuroblastoma: molecular docking, molecular dynamics, MM-PBSA binding energy, and in-vitro study. Journal of Biomolecular Structure and Dynamics, 40(23), 12827-12840. doi:10.1080/07391102.2021.1977705.

引用: https://hdl.handle.net/21.11116/0000-000A-398E-7

要旨

Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, primary regulator of various cellular activities varying from glycogen metabolism to cell proliferation and regulation. GSK-3β is associated with the pathogenesis of numerous human diseases, including cancer, metabolic disorder, and Alzheimer's disease. In this study, Azadirachta indica compounds were selected and further screened on the BOILED-Egg model. The compounds showing good GIT absorption were docked with the crystal structure of GSK-3β. The compounds with high docking score were submitted for the molecular dynamic simulation (MDS) and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA). Based upon the MDS and MM-PBSA study, gedunin showed the highest binding energy throughout the MDS process. Gedunin was isolated from the Azadirachta indica, and its efficacy on GSK-3β inhibition was studied in the human neuroblastoma (SH-SY5Y) cells. Gedunin induced apoptosis and anti-proliferative activity by arresting G2/M phase, as evident by cell-cycle analysis. From immunoblot study, gedunin significantly enhanced the expression of an inhibitory form of GSK-3β (p-GSK-3β Ser9) in concentration-dependent manner. Our findings demonstrate that gedunin may act as an effective GSK-3β inhibitor suggesting that this compound may be used for the management of neuroblastoma. Further preclinical and clinical investigation is desirable.