Understanding the mechanism of Trikatu in type 2 diabetes mellitus and lipid-related metabolic disorders: A network pharmacology approach

Abstract

Objective: Trikatu is an Indian polyherbal formulation comprising three herbs, i.e., Zingiber officinale, Piper longum, and Piper nigrum. It is traditionally used to treat metabolic disorders such as type 2 diabetes mellitus (T2DM), dyslipidemia, and obesity. However, its mechanism of action remains unknown. This study aims to explore the underlying therapeutic mechanism of Trikatu in T2DM and lipid metabolic disorders using network pharmacology (NP). Methods: Trikatu phytochemicals were retrieved from various databases and screened on the basis of druglikeness and oral bioavailability (>30%) score. Putative targets of the bioactive phytochemicals were identified using TargetNet, Similarity Ensemble Approach, and Swiss Target Prediction databases. Protein-protein interaction (PPI) network of overlapping targets of phytochemicals and metabolic disorders was constructed using NetworkAnalyst 3.0. The Bioactive Phytochemical-Target-Pathway (BP-T-P) network was constructed using cytoscape v3.8.2, and the key targets of Trikatu were analyzed by Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Results: Twenty bioactive phytochemicals and 102 targets of Trikatu were identified. PPI network and enrichment analysis showed that 51 targets of Trikatu phytochemicals such as RXRA, STAT3 and ESR1, GSK3B, TNF, NOS2/3 regulate pathways like insulin resistance, steroid hormone biosynthesis, regulation of lipolysis in adipocytes, adipocytokine & cGMP-PKG signalling pathways, arachidonic acid metabolism and bile secretion. The results were validated by molecular docking which showed that RXRA, STAT3 and ESR1 strongly interact with their ligands alpha gurjunene, beta-sitosterol, piperlongumine, genistein and E-beta carotene, respectively. Conclusion: Hence, the multiple target and multiple pathway approach of Trikatu can be further explored in pharmacokinetics / Pharmacodynamics studies.