biostudies-literatureUnknown19Eissa IHPrincess Nourah Bint Abdulrahman UniversityThe overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (<b>T-1-DOCA</b>). Firstly, <b>T-1-DOCA</b>'s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of <b>T-1-DOCA</b> against wild and mutant EGFR proteins. <b>T-1-DOCA</b>'s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, <b>T-1-DOCA</b> showed noticeable efficacy compared to erlotinib by suppressing EGFR^WT and EGFR^T790M with IC₅₀ values of 56.94 and 269.01 nM, respectively. <b>T-1-DOCA</b> inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC₅₀ values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of <b>T-1-DOCA</b> were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, <b>T-1-DOCA</b>, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that <b>T-1-DOCA</b> is a promising candidate for further development as an anti-cancer drug.Evolutionary bioinformatics online11769343231217916https://www.ebi.ac.uk/biostudies/studies/S-EPMC10693208biostudies-literatureComputer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer.PMC10693208Yousef RGElkady HIbrahim IMEl-Mahdy HAAlsfouk AAHusein DZElkaeed EBMetwaly AMEissa IHfalseComputer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer.The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (<b>T-1-DOCA</b>). Firstly, <b>T-1-DOCA</b>'s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of <b>T-1-DOCA</b> against wild and mutant EGFR proteins. <b>T-1-DOCA</b>'s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, <b>T-1-DOCA</b> showed noticeable efficacy compared to erlotinib by suppressing EGFR^WT and EGFR^T790M with IC₅₀ values of 56.94 and 269.01 nM, respectively. <b>T-1-DOCA</b> inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC₅₀ values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of <b>T-1-DOCA</b> were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, <b>T-1-DOCA</b>, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that <b>T-1-DOCA</b> is a promising candidate for further development as an anti-cancer drug.2023-01-01T00:00:00Z20232026-05-29T00:38:07.886Z2025-04-06T05:18:30.601ZS-EPMC106932083804665210.1177/11769343231217916