Elemol, a microbial-derived inhibitor of the HER۲ L۷۵۵S mutation and PI۳K/AKT signaling, for HER۲-positive breast cancer: an in silico study

Breast cancer is the most common malignancy among women and a leading cause of cancer-related mortality. The human epidermal growth factor receptor ۲ (HER۲)–positive subtype is particularly aggressive and often develops resistance to targeted therapies. The L۷۵۵S mutation in the tyrosine kinase domain of HER۲ contributes to this resistance and enhances metastatic potential. The mechanisms underlying this resistance and expanding effective treatments are major research challenges. The phosphatidylinositol-۳-kinase/protein kinase B (PI۳K/AKT) pathway is the basic way for apoptosis, which is frequently altered in cancers, plays a critical role in drug resistance and cellular proliferation. This signaling pathway activates various downstream pathways and displays complex interactions with other signaling networks. Ligand Elemol derived from microbial compound was evaluated in terms of its drug-likeness and pharmacokinetics properties. Via AutoDock Vina was performed Molecular docking, followed by molecular dynamics (MD) simulations. Elemol was screened compound as lead inhibitor with binding energies of _x۰۰۰۲_۰۸.۰۶ kcal/mol, respectively. It showed favorable oral bioavailability and high gastrointestinal absorption. MD simulations approved the stability of ligand-protein complex for Elemol. In L۷۵۵S mutation Elemol demonstrates structural stability, binding affinity and pharmacokinetic profile, positioning it as a promising candidate for L۷۵۵S-HER۲ targeted anti-cancer drug development.

کلیدواژه ها:

Breast Neoplasms (Cancer) ، HER۲ Protein ، Elemol ، L۷۵۵S mutation ، Molecular Dynamic Simulation