{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["19"],"submitter":["Eissa IH"],"funding":["Princess Nourah Bint Abdulrahman University"],"pubmed_abstract":["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<sup>WT</sup> and EGFR<sup>T790M</sup> with IC<sub>50</sub> 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 IC<sub>50</sub> 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."],"journal":["Evolutionary bioinformatics online"],"pagination":["11769343231217916"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10693208"],"repository":["biostudies-literature"],"pubmed_title":["Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer."],"pmcid":["PMC10693208"],"pubmed_authors":["Yousef RG","Elkady H","Ibrahim IM","El-Mahdy HA","Alsfouk AA","Husein DZ","Elkaeed EB","Metwaly AM","Eissa IH"],"additional_accession":[]},"is_claimable":false,"name":"Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer.","description":"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<sup>WT</sup> and EGFR<sup>T790M</sup> with IC<sub>50</sub> 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 IC<sub>50</sub> 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023","modification":"2026-05-29T00:38:07.886Z","creation":"2025-04-06T05:18:30.601Z"},"accession":"S-EPMC10693208","cross_references":{"pubmed":["38046652"],"doi":["10.1177/11769343231217916"]}}