Dataset Information

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

ABSTRACT: 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 IC₅₀ value of 17.23 nM for EGFR inhibition besides IC₅₀ 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 (IC₅₀ = 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.

SUBMITTER: Elkaeed EB

PROVIDER: S-EPMC9500845 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New Anticancer Theobromine Derivative Targeting EGFRWT and EGFRT790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies.

Elkaeed Eslam B EB Yousef Reda G RG Elkady Hazem H Alsfouk Aisha A AA Husein Dalal Z DZ Ibrahim Ibrahim M IM Metwaly Ahmed M AM Eissa Ibrahim H IH

Molecules (Basel, Switzerland) 20220909 18

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 (EGFRWT; PDB: 4HJO) and mutant (EGFRT790M; 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 dy ...[more]

PMID: 36144596

Similar Datasets

Project description:A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFRWT and EGFRT790M protein kinases, with IC50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFRWT and EGFRT790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFRWT and EGFRT790M, with binding scores of -6.40 kcal mol-1 and -7.53 kcal mol-1, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol-1, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFRWT and EGFRT790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.

Dataset Information

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

Publications

New Anticancer Theobromine Derivative Targeting EGFR<sup>WT</sup> and EGFR<sup>T790M</sup>: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets