In Silico Screening and Structural Optimization of Curcumin Derivatives with Potential Anticancer Activity

Lung cancer remains the leading cause of cancer-related deaths globally, responsible for 18.4% of the 9.6 million cancer deaths reported in 2018. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of cases, with epidermal growth factor receptor (EGFR) mutations representing key therapeutic targets. Although EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have shown clinical efficacy, acquired resistance within 12 months limits their long-term utility. To address this challenge, the present study focuses on the rational design of curcumin analogues as potential EGFR inhibitors using molecular modeling approaches. A series of nineteen curcuminoid derivatives were designed based on Structure-Activity Relationship (SAR) analysis, identifying electron-withdrawing groups (-Cl, -F, -NO₂) and electron-donating groups (-OMe, -OH) as influential substituents on the phenyl ring. Molecular docking studies against the EGFR kinase domain (PDB ID: 4I23) indicated that compounds 3, 2, and 17 exhibited the highest binding scores, interacting with key residues Met793, Lys745, and Asp855. Ortho-substitution enhanced binding over para-substitution. In vitro anticancer assays confirmed Compound 3 as the most active, with an IC₅₀ of 104 µM. These results highlight the potential of these novel curcuminoid derivatives for EGFR-targeted NSCLC therapy.