Molecular Docking, Molecular Dynamics Simulation, Network Pharmacology, and Therapeutic Potential of SIRT-1720 Against MPP+-induced Toxicity in SH-SY5Y Cells in Parkinson’s Disease: <i>In Vitro Studies</i>

Background: This study investigated the medicinal efficacy of SIRT-1720 in treating MPP[Formula: see text]-induced toxicity in the SHSY-5Y neuroblastoma cell line in Parkinson’s disease. SIRT-1720, an allosteric modulator of sirtuins, ameliorates mitochondrial activity during oxidative or cellular stress. Materials and methods: Target identification, molecular docking, molecular dynamic studies, gene enrichment and in vitro research involving neuroprotection studies are among the many investigations involving SHYS-5Y neuroblastoma cell lines. The cell viability significantly decreased to 27.50% because of the MPP[Formula: see text] toxicity generated at a dose of 0.5 mM. The effectiveness of SIRT-1720 was investigated at different concentrations, and at a concentration of 12.5 [Formula: see text]g/mL, resveratrol significantly increased cell viability to 88.3% and 77.7%, respectively. Results: The SIRT-1720-regulated domains were associated with 100 and 3581 disease-related targets, among which 4 common targets were screened: SIRT3, SOD2, FOXO1 and PPARGC1A. Gene enrichment and network analyses validated the neurological, mitochondrial and peroxisome system targeting of these genes. Among the 59 KEGG pathways, the “FoxO signaling pathway” modulates SIRT3, SOD2, FOXO1 and PPARGC1, with the highest edge counts (16), neighborhood connectivity (3.5) and degree layout (16). In AutoDock 4.0, SIRT-1720 was found to have the highest binding affinity with SIRT3, with maximum binding affinities of −8.55 and −8.04 kcal/mol. Compared with resveratrol, SIRT-1720 resulted in greater cell viability. In the MPP[Formula: see text]-induced group, SIRT3, FOXO1, GPx and PPARGC1A expression increased 0.87-, 0.80-, 0.87- and 0.75-fold, respectively. Compared with 1.5 U/mL, SIRT-1720 decreased LDH levels, with a fold change of 0.48. Conclusion: The results of the present study demonstrated that SIRT-1720 modulates critical ROS and mitochondrial biogenesis pathways, including the SIRT3, PGC-1[Formula: see text], SOD2 and FOXO1 pathways. Additionally, SIRT-1720 promoted high cell viability and increased target expression, which could slow the progression of Parkinson’s disease.