LC-MS/MS-guided profiling and network pharmacology analysis of bioactive compounds from Costus speciosus targeting type 2 diabetes: Insights from molecular docking and dynamics

Abstract

Background/objectives: Costus speciosus is a medicinal plant traditionally used in Southeast Asia for its metabolic and anti-inflammatory properties, yet the molecular mechanisms underlying its bioactivity remain underexplored. Among its phytoconstituents, various plant-derived lipophilic compounds have attracted attention due to their structural similarity to endogenous metabolites and their potential role in modulating metabolic pathways relevant to type 2 diabetes mellitus (T2DM). This study aimed to investigate the binding behavior and stability of Costus speciosus-derived metabolites against key molecular targets involved in insulin signaling and oncogenic transformation.

Methods: LC-MS/MS profiling was employed to identify major bioactive metabolites from the rhizome extract. Subsequently, a network pharmacology approach was used to filter relevant targets, followed by molecular docking and 200 ns molecular dynamics simulations to evaluate interaction stability. Binding free energy was computed using the MM-PBSA method to support thermodynamic relevance

Results: A total of 18 compounds were identified via LC-MS/MS, of which 15 were successfully linked to at least one protein target through bioinformatics databases and proceeded to molecular docking analysis. Among these, campestanol showing the highest docking affinity (-10.73 kcal/mol) and the lowest inhibition constant (13.60 nM) toward PIK3CA. Molecular dynamics simulations revealed that the PIK3CA-campestanol complex exhibited comparable or superior stability metrics (RMSD, RMSF, Rg, SASA, RDF, and hydrogen bonding) to the native ligand. MM-PBSA calculations confirmed robust van der Waals and hydrophobic contributions to binding, with total binding energy at -117.144 ±13.887 kJ/mol. These computational findings were further corroborated by prior experimental studies demonstrating campestanol's metabolic regulatory functions.

Conclusions: Campestanol demonstrates stable and favorable binding with PIK3CA, supporting its role as a promising candidate for further in vitro validation in metabolic and oncogenic pathway modulation. This study provides mechanistic insights into Costus speciosus bioactivity and strengthens the rationale for advancing campestanol as a lead compound in PI3K/AKT-targeted therapies for T2DM.

Keywords

Costus speciosus / Antidiabetic candidate / PI3K/AKT pathway / Metabolite profiling / Network pharmacology

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