Lung cancer targeting by trimethoxy flavans: a molecular simulation study.

Area of Science:

• Computational chemistry
• Drug discovery
• Oncology

Background:

• Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality.
• Novel therapeutic strategies are urgently needed to improve patient outcomes.
• Flavan derivatives have shown promise in various therapeutic areas.

Purpose of the Study:

• To evaluate the therapeutic potential of novel trimethoxyflavan derivatives against NSCLC using an integrated *in silico* approach.
• To identify lead compounds with high efficacy and favorable pharmacokinetic profiles.
• To provide a computational basis for further preclinical and clinical development.

Main Methods:

• Structure-based virtual screening and molecular docking against nine cancer-related protein targets.
• Molecular dynamics (MD) simulations at varying temperatures (300-320 K) to assess complex stability.
• MM/PBSA binding free-energy calculations, density functional theory (DFT) analysis, and ADMET profiling.
• Benchmarking against established drugs genistein and cianidanol.

Main Results:

• Compound 18 (N-(4-methoxyphenyl)-3-(5,6,7-trimethoxychroman-2-yl)benzamide) emerged as the most potent candidate.
• Compound 18 exhibited strong binding affinities for Keap1 (-9.1 kcal mol⁻¹) and HER2/erbB2 (-8.4 kcal mol⁻¹), surpassing reference drugs.
• MD simulations confirmed the stability of the Keap1-compound 18 complex, with reliable trajectory convergence.
• DFT and ADMET predictions indicated favorable electronic properties, bioactivity, and drug-like characteristics.

Conclusions:

• Compound 18 is a promising lead candidate for NSCLC therapy based on extensive *in silico* evaluation.
• The identified strong binding affinities and favorable pharmacokinetic profile support its potential clinical utility.
• Further *in vivo* validation is recommended to advance compound 18 towards clinical development.