LC-HRMS and In Silico Analysis of Ailanthus excelsa Metabolites Targeting EGFR Triple Mutation (L۸۵۸R/T۷۹۰M/C۷۹۷S)

The present study investigated the phytochemical composition and pharmacological potential of Ailanthus excelsa using a comprehensive approach that combined LC-HRMS analysis, molecular docking, and ADMET profiling. Using hydroalcoholic maceration extraction, a chemically rich extract was obtained from the leaves and bark of the plant. LC-HRMS analysis identified over ۶۰ distinct phytoconstituents, including flavonoids (quercetin, rutin, isoquercitrin, and kaempferol), and phenolic acids (gallic acid). Representative triterpenoid saponins (betulinic acid glycoside and soyasaponin I) and quassinoids (ailanthone and dehydroailanthone) were also detected. Following identification, these compounds were evaluated for their potential to inhibit the triple-mutant EGFR protein (L۸۵۸R/T۷۹۰M/C۷۹۷S), a major target of fourth-generation tyrosine kinase inhibitors (TKIs) in drug-resistant cancers. Molecular docking studies using AutoDock Vina revealed strong binding affinities for several metabolites, with dehydrodianthrone exhibiting the most favorable docking score of –۱۰.۴ kcal/mol. Other potent compounds such as kaempferol-۳-rutinoside (–۹.۳ kcal/mol), ailanthone (–۹.۵ kcal/mol), and rutin (–۹.۲ kcal/mol) also demonstrated significant interactions with key resistant residues MET۷۹۰ and ASP۸۵۵. ADMET analysis, performed using SwissADME and ADMETlab ۳.۰, confirmed favorable pharmacokinetic parameters for top-ranked compounds, including acceptable lipophilicity (logP), high intestinal absorption, low toxicity risks, and minimal CYP۴۵۰ enzyme inhibition. Dehydrodianthrone, in particular, combines potent docking interactions with strong ADMET characteristics, including favorable blood-brain barrier permeability and minimal toxicity. These findings collectively suggest that secondary metabolites from Ailanthus excelsa have potential as lead scaffolds for the development of fourth-generation EGFR inhibitors, providing an effective natural alternative against drug-resistant cancer targets. Further in vivo and in vitro investigations are warranted to validate these results and to facilitate drug development.

کلیدواژه ها:

Ailanthus excelsa ، Phytochemical profiling ، EGFR L۸۵۸R/T۷۹۰M/C۷۹۷S ، LC-HRMS ، Molecular docking ، ADMET analysis ، Natural EGFR inhibitors