Lung Cancer Targeting by Trimethoxy Flavans: A Molecular Simulation Study

Abstract

The therapeutic potential of a series of trimethoxy flavan derivatives (1-24) was evaluated for treating non-small cell lung cancer (NSCLC) through a comprehensive in silico investigation. The study employed density functional theory (DFT) calculations, molecular docking against nine target proteins, molecular dynamics (MD) simulations, and biological activity predictions using PASS (Prediction of Activity Spectra for Substances) and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. The performance of these derivatives was benchmarked against two reference drugs, genistein and cianidanol. Among the compounds, compound 18-N-(4-methoxyphenyl)-3-(5,6,7-trimethoxychroman-2-yl)benzamide emerged as the most promising candidate, demonstrating strong binding affinities with critical target proteins, including Keap1 (PDB: 1X2J; -9.1 kcal/mol) and human HER2/erbB2 (PDB: 3PP0; -8.4 kcal/mol), surpassing the reference drugs. MD simulations at multiple temperatures (300, 305, 310, and 320 K) confirmed the stability of compound 18's protein interactions, as reflected by favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) profiles. Furthermore, principal component analysis (PCA) revealed ~86% convergence at 310 K, indicating consistent dynamic behavior. These computational findings, supported by available in vitro evidence, highlight compound 18 as a promising drug candidate for NSCLC therapy. Further in vivo investigations are warranted to validate its clinical potential.