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New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR(WT); PDB: 4HJO) and mutant (EGFR(T790M); PDB: 3W2O) types of EGFR-TK indicated that the designed...

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Autores principales: Elkaeed, Eslam B., Yousef, Reda G., Elkady, Hazem, Alsfouk, Aisha A., Husein, Dalal Z., Ibrahim, Ibrahim M., Metwaly, Ahmed M., Eissa, Ibrahim H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500845/
https://www.ncbi.nlm.nih.gov/pubmed/36144596
http://dx.doi.org/10.3390/molecules27185859
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author Elkaeed, Eslam B.
Yousef, Reda G.
Elkady, Hazem
Alsfouk, Aisha A.
Husein, Dalal Z.
Ibrahim, Ibrahim M.
Metwaly, Ahmed M.
Eissa, Ibrahim H.
author_facet Elkaeed, Eslam B.
Yousef, Reda G.
Elkady, Hazem
Alsfouk, Aisha A.
Husein, Dalal Z.
Ibrahim, Ibrahim M.
Metwaly, Ahmed M.
Eissa, Ibrahim H.
author_sort Elkaeed, Eslam B.
collection PubMed
description Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR(WT); PDB: 4HJO) and mutant (EGFR(T790M); PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC(50) value of 17.23 nM for EGFR inhibition besides IC(50) values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC(50) = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis.
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spelling pubmed-95008452022-09-24 New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies Elkaeed, Eslam B. Yousef, Reda G. Elkady, Hazem Alsfouk, Aisha A. Husein, Dalal Z. Ibrahim, Ibrahim M. Metwaly, Ahmed M. Eissa, Ibrahim H. Molecules Article Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR(WT); PDB: 4HJO) and mutant (EGFR(T790M); PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC(50) value of 17.23 nM for EGFR inhibition besides IC(50) values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC(50) = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis. MDPI 2022-09-09 /pmc/articles/PMC9500845/ /pubmed/36144596 http://dx.doi.org/10.3390/molecules27185859 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elkaeed, Eslam B.
Yousef, Reda G.
Elkady, Hazem
Alsfouk, Aisha A.
Husein, Dalal Z.
Ibrahim, Ibrahim M.
Metwaly, Ahmed M.
Eissa, Ibrahim H.
New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title_full New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title_fullStr New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title_full_unstemmed New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title_short New Anticancer Theobromine Derivative Targeting EGFR(WT) and EGFR(T790M): Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies
title_sort new anticancer theobromine derivative targeting egfr(wt) and egfr(t790m): design, semi-synthesis, in silico, and in vitro anticancer studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500845/
https://www.ncbi.nlm.nih.gov/pubmed/36144596
http://dx.doi.org/10.3390/molecules27185859
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