Ashwagandharishta compounds possess affinity interactions against diabetes-linked liver cancer: Implications from network pharmacology, molecular docking and dynamics simulations

Abstract

Ashwagandharishta represents the Ayurvedic polyherbal fermented traditional medicine (FTM) and it contains Withania somnifera (L.) Dunal. is the principal herb. The present study employs network pharmacology analysis in identifying the single target Vs. multiple interacting partners in establishing the Ashwagandharishta as a potent inhibitory agent. The interacting phytoconstituents were assessed for target protein interaction patterns involved in diabetes-associated liver cancer. By GC–MS, 89 phytocompounds and derivatives of Ashwagandharishta were extracted, and 34 were scrutinized using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). The present seqeuale corresponds to additional curation from DisGeNET and GeneCards databases. Seventeen phytocompounds and 169 targets were scrutinized for potential links between diabetes and liver cancer. Among the 17 compounds, seven exhibited increased binding affinities with target proteins that are mainly associated with diabetes and liver cancer. The target signaling interactions between diabetes and liver cancer were ascertained using Gene Ontology and KEGG databases. Retusine, stigmasterol, and 6,7-Isoquinolinediol, 1,2,3,4-tetrahydro-1-methyl exhibited significant hydrogen bonding interactions and affinity scores when docked with top hub genes. In molecular dynamics simulations, retusine-JUN bound complexes revealed potential stability at 200 ns. MM-GBSA results showed that thermal energy did not impact protein-ligand complex binding free energies, notably in MD simulated complexes, demonstrating strong ligand-protein interactions. The authenticity of bioactive compounds in Ashwagandharishta was analyzed for multiple protein target interactions. Moreover, the rational approach based on computational analyses will aid in concluding the molecular mechanisms backing the proven facts of FTM shortly.