Molecular Insights into Identification of Natural AKT1/mTOR Signaling Inhibitors from Veratrum Viride-Derived Alkaloids for Breast Cancer Treatment: A Comprehensive Analysis Using Network Pharmacology, Molecular Docking, and Molecular Dynamics.

Abstract

Objective: Breast cancer (BC) is a complex illness that affects millions of women globally. As its incidence rises, new treatment strategies are needed. Veratrum viride, a traditional medicinal herb, is known for its therapeutic potential, yet its molecular mechanism of action against BC remains unclear. The purpose of this preliminary investigation is to assess V. viride's anti-breast cancer potential by identifying its active compounds and using bioinformatics techniques to clarify their multi-target mechanisms.

Materials & methods: Initially, eleven compounds from V. viride were examined for pharmacokinetic and toxicity characteristics. Network pharmacology was used to predict and integrate compound-target interactions with genes linked to BC. Topological and drug-protein interaction (DPI) analyses were employed to identify important hub genes. KEGG pathway enrichment and Gene Ontology (GO) analyses were conducted to validate functional relevance. Target-compound interactions were verified through molecular docking and molecular dynamics simulation analysis.

Results:  Using ADMET profiling analysis and drug-likeness properties, three alkaloids namely jervine, veratramine, and rubijervine were identified as promising drug candidates. We identified six important hub genes: MTOR, INSR, FOXO1, FOXO3, RPS6KB1, and AKT1. According to GO and KEGG analyses, the compounds targeted pathways important in the regulation of BC, including AMPK, HIF-1, FOXO, and PI3K/AKT/mTOR. Moreover, jervine demonstrated robust binding stability and affinity with core targets in molecular docking and dynamics simulations.

Conclusion: This work provides the first evidence that alkaloids derived from V. viride, especially jervine, may act as multi-target inhibitors against BC. However, further experimental validation is required to confirm their therapeutic efficacy.