In-Silico Screening, ADME Prediction and Molecular Dynamics Simulations of Curcuminoid Derivatives Targeting EGFR

Epidermal growth factor receptor (EGFR) protein kinase is a pivotal target in cancer therapy due to its overexpression in various malignancies, including lung, breast, and prostate cancers. Although the FDA has approved several ATP-competitive EGFR inhibitors, their efficacy is often compromised by mutations like T790M and L858R, which enhance ATP affinity and reduce drug binding, thereby further reducing the efficacy of first- and second-generation inhibitors. To overcome these challenges, we aimed to design and evaluate novel curcuminoid derivatives that could potentially serve as more effective EGFR inhibitors.

We designed new curcuminoid derivatives based on an extensive literature review and structure-activity relationship (SAR) analysis. Molecular docking studies were conducted to assess the binding affinities and interaction patterns of these compounds with the EGFR kinase domain. ADME properties were predicted according to Lipinski's Rule of Five. The stability and dynamics of the top-performing compounds were further analysed using molecular dynamics (MD) simulations.

The in-silico studies revealed that compounds with ortho substitutions on the phenyl ring, particularly -Br, -NO2, and -OCH3, exhibited the strongest binding affinities. Notably, compounds 3, 2, and 17 achieved docking scores of -7.23, -7.22, and -7.06, respectively. Additionally, MD simulations confirmed the stability of the Compound 3-EGFR complex, emphasizing the critical role of the α-β-unsaturated ketone aliphatic chain in binding to Met793.

The novel curcuminoid derivatives designed in this study showed strong potential as EGFR inhibitors, with Compound 3 demonstrating superior docking scores and conformational stability comparable to the reference standard, Dacomitinib. These findings suggest that these derivatives could be promising candidates for further development as cancer therapeutics.