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Mutant-Selective Binding of Phyllanthus niruri Phytochemicals to EGFR T790M: A Quantum-Classical Mechanistic Study
William D Lituma-González1, Diksha Dinesh Kumar1, Amogh V Arunprasad1
1Department of Integrative and Transdisciplinary Pharmacognosy, Siddha Vetha University, 211 Warren st, Newark, NJ 07103, USA.
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 largest MM-PBSA electrostatic term (ΔEele = -52.48 kcal/mol), establishing quantum-classical coherence. Supervised PCA/LDA of 7416 MM-PBSA trajectory frames identified solvation energy (ΔGSOLV) as the primary pharmacological class discriminant, with the first discriminant function (LD1) capturing 93.1% of inter-class binding variance. Collectively, corilagin (hydrolyzable tannin), eriodictyol-7-rhamnopyranoside (flavonoid glycoside), and phyltetralin (lignan) constitute diverse computational leads from P. niruri warranting experimental validation as T790M-directed agents in HCC.
Insights
Phyllanthus niruri phytochemicals show promise as novel non-covalent inhibitors for the T790M mutation in Epidermal Growth Factor Receptor (EGFR), a key driver in hepatocellular carcinoma (HCC) resistance. Corilagin demonstrated superior binding affinity and selectivity, warranting further investigation for HCC treatment.
Area of Science:
- Computational chemistry and molecular modeling
- Pharmacology and drug discovery
- Oncology and cancer research
Background:
- Epidermal growth factor receptor (EGFR) mutations, particularly the T790M substitution, are critical in hepatocellular carcinoma (HCC) progression and confer resistance to targeted therapies.
- Identifying novel therapeutic agents that can overcome T790M-mediated resistance is crucial for improving HCC patient outcomes.
Purpose of the Study:
- To computationally predict the potential of Phyllanthus niruri phytochemicals as non-covalent inhibitors targeting the EGFR T790M mutation.
- To evaluate the binding affinity, selectivity, and underlying mechanisms of these phytochemicals against wild-type and mutant EGFR.
Main Methods:
- Multiscale quantum-classical simulations including molecular docking, 100 ns molecular dynamics, MM-PBSA/MM-GBSA, and DFT calculations (B3LYP-D3(BJ)/def2-TZVP).
- Comparative simulations with wild-type EGFR (PDB 1M17) and osimertinib for methodological validation.
- Principal Component Analysis/Linear Discriminant Analysis (PCA/LDA) for analyzing binding trajectory frames.
Main Results:
- Five Phyllanthus niruri phytochemicals, including corilagin, eriodictyol-7-rhamnopyranoside, isoquercetin, rutin, and kaempferol-4-rhamnoside, exhibited predicted binding affinities exceeding osimertinib's non-covalent binding component.
- Corilagin demonstrated significant T790M-preferential binding (Selectivity Index = 2.76), validated by its strong electrostatic affinity predicted via DFT.
- Solvation energy was identified as the primary discriminant for binding affinity differences among the studied compounds.
Conclusions:
- Phyllanthus niruri phytochemicals, particularly corilagin, eriodictyol-7-rhamnopyranoside, and phyltetralin, represent promising computational leads for developing novel T790M-directed agents against HCC.
- The study establishes quantum-classical coherence for corilagin's binding mechanism, highlighting its potential therapeutic value.
- Experimental validation of these identified phytochemicals is warranted for their application in HCC treatment strategies.
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