Computational Exploration of 4-Hydroxy-3-Methoxycinnamic Acid Derivatives Derived from Natural Product Scaffolds for Anticancer Activity

Abstract

Objective: This study seeks to investigate 4-hydroxy-3-methoxycinnamic acid (Ferulic acid) derivatives using computational approaches—specifically Lipinski’s Rule of Five, ADMET profiling, Mol-Inspiration analysis, and molecular docking—in order to evaluate their drug-likeness, pharmacokinetic properties, and therapeutic potential, with a particular focus on lung cancer treatment. Methodology: The study examined the physicochemical, pharmacokinetic, and pharmacodynamic properties of 4-hydroxy-3-methoxycinnamic acid derivatives substituted with aromatic amines through in-silico approaches. Computational analyses were performed using web-based tools and specialized programs, including Pre-ADMET, Mol-Inspiration, and Molegro Virtual Docker 6.0. Result and Discussion: Computational evaluation of 15 aromatic amine–substituted 4-hydroxy-3-methoxycinnamic acid (Ferulic acid) derivatives demonstrated favourable drug-likeness, as confirmed by Mol-Inspiration analysis and compliance with Lipinski’s Rule of Five. ADMET predictions indicated promising pharmacokinetic behaviour with minimal toxicity risks. Molecular docking against tyrosine kinase targets (PDB IDs: 4ZSE, 8A27, 5T4B, 6CU6) revealed strong binding affinities, with 6CU6 showing the most significant interactions suggestive of inhibitory potential. Key binding modes included hydrogen bonding and π–π stacking with active site residues, underscoring the suitability of these derivatives as potential lead candidates for lung cancer therapy.The test compound FA-6 exhibited the highest binding affinity with a MolDock score of −172.892, forming multiple hydrogen-bond interactions with Ala 146, Lys 147, Asp 119, Thr 35, Ser 17, Asp 33, Tyr 32, Arg 12, Gly 60, and Lys 16 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: This study demonstrates that the selected 4-hydroxy-3-methoxycinnamic acid(Ferulic acid)derivatives possess favourable ADMET profiles, strong drug-likeness, and notable tyrosine kinase inhibitory activity. These findings highlight their promise as potential lead candidates for the development of lung cancer therapeutics.