T-1-PA

Epidermal Growth Factor Receptor (EGFR) is a well-established therapeutic target in cancer treatment. In this study, a novel N-phenylacetamide derivative of theobromine, designated as T-1-PA, was designed as a potential semisynthetic EGFR inhibitor.

The 3D structure, stability, and electronic reactivity of T-1-PA were determined using Density Functional Theory (DFT) analyses. Molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), Protein–Ligand Interaction Profiler (PLIP), and Principal Component Analysis of Trajecto-ries (PCAT) were employed to evaluate the binding affinity and inhibitory potential of T-1-PA against EGFR. Computational ADMET profiling was conducted to predict drug-likeness and safety. Subsequently, T-1-PA was semisynthesized and subjected to in vitro biological evaluation.

Computational analyses demonstrated a strong binding affinity of T-1-PA to EGFR. The compound exhibited favorable ADMET properties. In vitro assays revealed po-tent EGFR inhibition with an IC50 of 0.736 ± 0.005 µM. T-1-PA also inhibited the prolifer-ation of HepG2 and MCF7 cancer cell lines with IC50 values of 0.88 ± 0.01 µM and 1.13 ± 0.01 µM, respectively. Flow cytometry analysis indicated induction of apoptosis and G1 phase cell cycle arrest in HepG2 cells. Additionally, T-1-PA significantly impaired HepG2 cell migration and wound-healing capacity.

The results validate the computational predictions and highlight the anticancer potential of T-1-PA through EGFR inhibition and antiproliferative activity. The compound';s favorable pharmacokinetic and safety profiles further support its therapeutic promise.

T-1-PA is a promising semisynthetic compound with selective antiproliferative activity mediated via EGFR inhibition. These findings encourage further preclinical inves-tigation of T-1-PA as a novel candidate for EGFR-targeted cancer therapy.