Integrated In Silico and In Vitro Investigation of Novel Curcuminoid Hybrids as Potent EGFR L858R/T790M Inhibitors with Favorable Toxicity and Antioxidant Profiles

The epidermal growth factor receptor (EGFR) is a well-validated therapeutic target in non-small cell lung cancer (NSCLC), particularly in drug-resistant L858R/T790M mutations. In this study, seventeen novel curcuminoid derivatives were rationally designed using in silico approaches, including structure–activity relationship (SAR) analysis, ADMET predictions, molecular docking, and molecular dynamics (MD) simulations. Among these, three compounds (3, 2, and 17) demonstrated superior binding affinities (docking scores: –7.23, –7.22, –7.06 kcal/mol) compared to the standard inhibitor dacomitinib (–6.03 kcal/mol). MD simulations further confirmed their stable interactions with key residues (Met793, Lys745, Asp855) within the EGFR active site. AI-based toxicity models predicted lower systemic toxicity and reduced carcinogenicity risks for compounds 3 and 17 relative to existing EGFR inhibitors. In vitro enzymatic assays validated the computational predictions, revealing potent inhibitory activity with IC₅₀ values of 104, 107, and 113 nM for compounds 3, 2, and 17, respectively, versus 114 nM for dacomitinib. Additionally, DPPH radical scavenging assays established significant antioxidant capacity, with Compound 2 surpassing ascorbic acid in potency. Collectively, the integration of computational and experimental approaches successfully identified curcuminoid derivatives as promising EGFR L858R/T790M inhibitors with favorable toxicity and antioxidant profiles. These findings highlight Compounds 3 and 17 as lead candidates for further preclinical evaluation, while Compound 2 emerges as a valuable antioxidant scaffold, underscoring the therapeutic potential of curcuminoid-based hybrids.