Exploring the therapeutic mechanism of potential phytocompounds from Kalanchoe pinnata in the treatment of diabetes mellitus by integrating network pharmacology, molecular docking and simulation approach

[Display omitted] •Potent inhibitory activity of alpha-amylase and alpha-glucosidase by K. pinnata was evidenced in dose dependent manner.•Network pharmacology highlights the significant edge count for kaempferol and luteolin considering their prominence as potential therapeutic agents.•MD confirms binding affinity of ligands with AMY2A, GAA, AR and DPP4.•MDS confirmed stability and structural configuration of AMY2A with friedelin and acarbose. Since ancient times, bioactive phytocompounds from different parts of medicinal plants have been used to heal various disease ailments and they are now regarded as a valuable source of disease prevention globally.Kalanchoe pinnatais a member of the Crassulaceae family; it has a long history of usage in traditional ayurvedic treatment. Analysis of bioactive compounds for their potential anti-type-2 diabetes mellitus (T2DM) mechanism along within-vitroandin-silicoapproaches was studied in the present research. The alpha-amylase and alpha-glucosidase inhibitory activity of methanolic extract of Kalanchoe pinnata (α-amylase: IC50 29.50 ± 0.04 μg/ml; α-glucosidase IC50 32.04 ± 0.35 μg/ml) exhibit a high degree of similarity to the standard drug acarbose (IC50 35.82 ± 0.14 μg/ml). Different biological databases were used to list phytocompounds from the plant, and ADME analysis using swissADME was carried out to screen compounds that obeyed the Lipinski rule of 5 and were employed further. STRING and KEGG pathway analysis was performed for gene enrichment analysis followed by network pharmacology to identify key target proteins involved in DM. AMY2A, NOX4, RPS6KA3, ADRA2A, CHRM5, and IL2 were identified as core targets for luteolin, kaempferol, alpha amyrin, stigmasterol compounds by modulating neuroactive ligand interaction, P13-AKT, MAPK, and PPAR signaling pathways. Molecular docking was performed to study the binding affinity among bioactive compounds ofK. pinnataagainst aldose reductase, alpha-amylase, alpha-glucosidase, and dipeptidyl peptidase IV. Alpha-amylase-friedelin [FRI] and alpha-amylase-acarbose [STD] complexes were subjected to molecular simulation for a 200 ns duration that depicted the stability of the compounds and proteins. In the current study, employing dual approach in-silico and in-vitroenzyme assays has yielded a comprehensive and strong understanding of its potential therapeutic properties, making a significant step towards the development of novel anti-diabetic treatment.