Mutant-Selective Binding of Phyllanthus niruri Phytochemicals to EGFR T790M: A Quantum-Classical Mechanistic Study
Abstract
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 (ΔΔGbind = +34.22 kcal/mol), indicating T790M-preferential binding. Osimertinib reproduced its clinically established T790M selectivity under identical conditions (IS = 1.43; ΔΔGbind = +7.74 kcal/mol), providing internal methodological validation. DFT at B3LYP-D3(BJ)/def2-TZVP established the quantum-mechanical basis for corilagin's electrostatic affinity: its molecular electrostatic potential (MEP) surface minimum (Vs,min = -46.92 kcal/mol) directly predicts the…
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