In silico discovery of novel microbial inhibitors targeting the L۷۵۵S mutation of human epidermal growth factor receptor ۲ (HER۲) in breast cancer

Breast cancer remains the leading malignancy among women globally, with HER۲-positive subtypes characterized by aggressive progression and therapeutic resistance. The L۷۵۵S mutation within the HER۲ tyrosine kinase domain confers resistance to conventional targeted therapies through enhanced metastatic signaling and reduced drug sensitivity. This study employed integrated computational methodologies combining structure-based virtual screening, molecular docking, ADME-Tox profiling, and extensive molecular dynamics simulations to identify microbial-derived inhibitors targeting wild-type and L۷۵۵S mutant HER۲. From an initial library of ۱۸۵ compounds, systematic pharmacological filtering yielded ۱۵ candidates subjected to molecular docking, revealing Elemol and Chloramphenicol as lead compounds with binding energies of -۸.۰۶ and -۷.۷۱ kcal/mol respectively against the L۷۵۵S mutant. Comprehensive ۲۰۰-nanosecond molecular dynamics simulations validated binding stability through RMSD analysis (۰.۲۷۵-۰.۳۲۹ nm), with MM-PBSA calculations confirming favorable energetics (-۷۹.۸ to -۱۱۵.۷ kJ/mol) dominated by van der Waals interactions. Elemol demonstrated mutation-selective binding through consistent Thr۸۶۲ hydrogen bonding and enhanced hydrophobic packing, while Chloramphenicol exhibited pan-HER۲ activity via adaptable interaction networks. Both compounds displayed favorable pharmacokinetic profiles with P-glycoprotein inhibition, low hERG risk, and absence of CYP۴۵۰ interference. These findings establish Elemol and Chloramphenicol as promising therapeutic candidates for HER۲-positive breast cancer, particularly drug-resistant variants, warranting experimental validation through biochemical and cellular assays.

کلیدواژه ها:

Breast Neoplasms (Cancer) ، HER۲ Protein ، L۷۵۵S mutation ، drug resistance ، molecular dynamics simulation