Network Pharmacology Approach and Molecular Docking Prediction to Investigate the Possible Mechanism of Benzylidene Derivatives Against Scavenging Reactive Oxygen Species via Sirtuin 3 in Parkinson's Disease

Abstract

Benzylidene derivatives have been extensively used to treat Parkinson's disease (PD). Various in-vitro and in-vivo studies on benzylidene have been shown to reduce oxidative stress and have resulted in neuroprotective effects. In addition, the mechanism of action of the therapeutic agents used in treating PD is unclear. Therefore, this study aims to investigate the potential molecular pathways behind antiparkinsonian activity by employing a network pharmacology approach.Various open-source databases were used in the designing of benzylidene derivatives. The virtual screening was performed for the hit-designed compounds by the putative targets implicated in PD development. The drug-likeness score, ADMET studies, and probable adverse effects were also predicted using admet SAR 2.0 and ADVERpred database. The regulated pathways were predicted using the Kyoto Encyclopedia of Genes database (KEGG). Among the designed 10 compounds (BH-1 to BH-10), the BH-1 compound was found to modulate proteins that are implicated in the progression of PD using Cytoscape 3.7.2. The further conformational analysis of the compounds was performed using molecular docking, MMGBSA, and molecular dynamics studies using the Schrödinger suite 2022. The designed compound BH-1 was determined to have the highest number of edge counts and was determined to have the highest docking score of-7.463 kcal/mol, with the highest MMGBSA score of-59.55 kcal/mol. Further, the network between the designed compounds, pathway, and gene, the FoxO signaling pathway, was found to be the most regulated pathway. The newly designed compounds have been found to exhibit significant potent results as compared to the standard molecule resveratrol. The findings suggested that the designed compound BH-1 could be a potential therapeutic agent in the treatment of PD.