In Silico Investigation of 4-hydroxy-3-Methoxycinnamic Acid Derivatives as Inhibitors of Key Oncogenic Targets Using Molecular Docking and ADMET Analysis
Prabhat Kumar Das *
Department of Pharmaceutical Chemistry, GRY Institute of Pharmacy, Borawan, Khargone, India.
Nitin Deshmukh
Department of Pharmaceutical Chemistry, GRY Institute of Pharmacy, Borawan, Khargone, India.
Saniya Karma
Department of Pharmaceutical Chemistry, GRY Institute of Pharmacy, Borawan, Khargone, India.
Viraj Aachary
Department of Pharmacognosy, GRY Institute of Pharmacy, Borawan, Khargone, India.
Shruti Yadav
Department of Pharmacognosy, GRY Institute of Pharmacy, Borawan, Khargone, India.
Priyanka Kumawat
Department of Pharmacognosy, GRY Institute of Pharmacy, Borawan, Khargone, India.
*Author to whom correspondence should be addressed.
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.
Keywords: Lung cancer, 4-hydroxy-3-methoxycinnamic acid, ADMET, mol-inspiration, molecular docking