Molecular bioprospection of Helianthus annuus L. (sunflower) cypselae for antidiabetic therapeutics through network pharmacology, density functional theory and molecular dynamics simulation

Abstract

Helianthus annuus cypsela (sunflower) is a staple oilseed crop with significant therapeutic applications against diverse diseases including type 2 diabetes mellitus (T2DM). Despite its reported antidiabetic potential, the implicated molecular mechanism of action is yet to be unravelled to date. This study evaluated the molecular mechanism of the antidiabetic activity of sunflower cypsela using network pharmacology (NP), density functional theory, and molecular dynamics (MD) simulation approaches. The six cultivars of sunflower cypsela used were profiled for their secondary metabolites using LC-MS and GC–MS techniques. Subsequently, the genes associated with the identified metabolites were screened against T2DM-associated genes using NP. Based on the KEGG enrichment analysis of the identified common genes, signaling pathways were subsequently identified. The results obtained revealed 87 intersecting genes between the metabolites of sunflower cypsela and T2DM, while the KEGG analysis identified 35 signaling pathways with the PPAR route and its associated genes as the most implicated in T2DM progression with respect to sunflower cypsela. Both MMP1 and PPARA in the PPAR pathways interacted most with the identified metabolites, with CGA (−43.74 kcal/mol), GPA (−41.62 kcal/mol), and CFG (−45.36 kcal/mol) having higher binding free energy than both ROS and MET (reference standards) against MMP1 after 100,000 ps MD simulation. In contrast, ROS (−46.98 kcal/mol) had better affinity against PPARA compared to the top hits of sunflower cypsela. However, against both gene targets, the top hits had significant thermodynamic stability, flexibility, and compactness, which are attributable to their bond interactions and molecular orbital properties. These findings are suggestive of the essential role of the top-hits in the antidiabetic potential of sunflower cypsela through activation of the PPAR signalling pathway and most especially MMP1. In this regard, the modulation of MMP1 and PPARA genes by the identified metabolites of sunflower cypsela may enhance insulin sensitivity and glucose homoeostasis in the management of T2DM.