Mutant-Selective Binding of Phyllanthus niruri Phytochemicals to EGFR T790M: A Quantum-Classical Mechanistic Study

Epidermal growth factor receptor (EGFR) mutations drive hepatocellular carcinoma (HCC) progression, and the T790M gatekeeper substitution is the predominant mechanism of acquired resistance to EGFR-targeted therapies. Herein, we present multiscale quantum-classical in silico predictions of Phyllanthus niruri phytochemicals as non-covalent EGFR T790M binders, employing molecular docking, 100 ns molecular dynamics, MM-PBSA/MM-GBSA, per-residue decomposition, PCA/LDA, DFT at B3LYP-D3(BJ)/def2-TZVP, and comparative wild-type EGFR simulations. Five phytochemicals exhibited computationally predicted binding affinities against EGFR T790M exceeding the non-covalent binding component of osimertinib (−25.74 kcal/mol): corilagin (−53.71 ± 5.05 kcal/mol), eriodictyol-7-rhamnopyranoside (−44.35 ± 4.51 kcal/mol), isoquercetin (−44.23 ± 2.92 kcal/mol), rutin (−42.15 ± 4.50 kcal/mol), and kaempferol-4-rhamnoside (−41.68 ± 3.69 kcal/mol). Wild-type EGFR simulations (PDB 1M17) yielded a selectivity index (IS) of 2.76 for corilagin (<!-- MathType@Translator@5@5@MathML2 (no namespace).tdl@MathML 2.0 (no namespace)@ -->