Analisis Network Pharmacology, Molecular Docking, dan Molecular Dynamics Senyawa Bisbenzylisoquinoline dari Genus Stephania terhadap Kanker Hati

Abstract

Background: Liver cancer is the fourth leading cause of cancer-related death worldwide. Chemotherapy has limited effectiveness and often causes severe side effects, highlighting the need for safer therapeutic alternatives. Bisbenzylisoquinoline (BBI) compounds from the Stephania genus have shown anticancer potential, yet their molecular targets against liver cancer remain poorly explored. Objective: This study aims to explore the anticancer potential of bisbenzylisoquinoline compounds from the Stephania genus against liver cancer using an in silico approach. Methods: The candidate compounds were evaluated for their predicted biological activity and pharmacokinetics using PASSOnline and SwissADME. Selected compounds were further analyzed through network pharmacology, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment to identify target proteins. Molecular docking was performed using AutoDock Vina, and the best ligand–receptor complex was further simulated using YASARA-based molecular dynamics for 100 ns. Results: Network pharmacology analysis identified two key targets, AKT1 and PI3K, which play essential roles in hepatocellular carcinoma signaling pathways. Molecular docking results showed that all 11 compounds exhibited lower binding affinity scores compared to sorafenib against AKT1, with four of them occupying the same binding pocket as the native ligand. For PI3K, 10 out of 11 compounds demonstrated lower binding affinity scores than sorafenib; however, only one compound was found to bind within the same pocket as the native ligand. Molecular dynamics simulation of the AKT1–isotrilobine complex over 100 ns revealed a stable interaction, characterized by low RMSD values, minimal RMSF fluctuations at the active site, consistent radius of gyration (Rg) and SASA values, stable hydrogen bonding, and the highest MM-PBSA binding energy of 70.61 kJ/mol. Conclusion: Isotrilobine shows promise as a potential anticancer candidate against liver cancer through stable interactions with the target protein AKT1. This study provides a preliminary scientific basis for the development of liver cancer therapies based on natural compounds.