In Silico Investigation of 4-hydroxy-3-Methoxycinnamic Acid Derivatives as Inhibitors of Key Oncogenic Targets Using Molecular Docking and ADMET Analysis

Abstract

Objective: This study aims to evaluate derivative of 4-hydroxy-3-methoxycinnamic acid through computational methods, including Lipinski’s Rule of Five, ADMET prediction, Mol-inspiration analysis and molecular docking to assess its drug-likeness, pharmacokinetics, and therapeutic potential for cancer treatment specially lung cancer. Methodology: This work assessed the physicochemical, pharmacokinetic, and pharmacodynamic characteristics of 4-hydroxy-3-methoxycinnamic acid substituted with aromatic amine using in-silico web tools using programs like Pre-ADMET, Mol-inspiration and Molegro Virtual Docker 6.0. Result and discussion: The computational analysis of 15 aromatic amine-substituted 4-hydroxy-3-methoxycinnamic acid derivatives revealed promising drug-likeness via Mol-inspiration and Lipinski’s Rule of Five compliance. ADMET profiling indicated favourable pharmacokinetics and low toxicity. Molecular docking against tyrosine kinase targets (PDB: 4ZSE, 8A27, 5T4B, 6CU6) showed strong binding affinities, particularly with 6CU6, suggesting potential inhibitory activity. Key interactions involved hydrogen bonding and π-π stacking with active site residues, supporting their candidacy as lead compounds for lung cancer therapeutics. The test compound FA-11 exhibited the highest binding affinity with a MolDock score of −181.092, forming multiple hydrogen-bond interactions with Asp33, Ser17, Thr35, Thr32, Arg12, Ser145, Lys147, and Asp119, indicating strong and stable binding within the active site. In comparison, the standard drug gefitinib showed a lower MolDock score (−157.872) with fewer hydrogen-bond interactions (Thr35, Ser17, and Glu31). Overall, FA-11 demonstrated superior docking performance compared to gefitinib and other tested ligands, highlighting its potential as a promising lead compound. Conclusion: The study concludes that selected 4-hydroxy-3-methoxycinnamic acid derivatives exhibit favourable ADMET, drug-likeness, and strong tyrosine kinase inhibition, highlighting their potential as promising candidates for lung cancer therapy.