Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors
Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this s...
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MDPI AG
2019-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/6/1092 |
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| author | Kanyani Sangpheak Lueacha Tabtimmai Supaphorn Seetaha Chompoonut Rungnim Warinthorn Chavasiri Peter Wolschann Kiattawee Choowongkomon Thanyada Rungrotmongkol |
| author_facet | Kanyani Sangpheak Lueacha Tabtimmai Supaphorn Seetaha Chompoonut Rungnim Warinthorn Chavasiri Peter Wolschann Kiattawee Choowongkomon Thanyada Rungrotmongkol |
| author_sort | Kanyani Sangpheak |
| collection | DOAJ |
| description | Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones <b>1c</b>, <b>2a</b>, <b>3e</b>, <b>4e</b>, and <b>4t</b> showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC<sub>50</sub> values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (<b>1c</b>, <b>2a</b> and <b>3e</b>) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors. |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-13T01:23:25Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-aa41dcafb2f04bd585310f2787065f252022-12-22T03:08:41ZengMDPI AGMolecules1420-30492019-03-01246109210.3390/molecules24061092molecules24061092Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase InhibitorsKanyani Sangpheak0Lueacha Tabtimmai1Supaphorn Seetaha2Chompoonut Rungnim3Warinthorn Chavasiri4Peter Wolschann5Kiattawee Choowongkomon6Thanyada Rungrotmongkol7Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10903, ThailandDepartment of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10903, ThailandNational Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, ThailandCenter of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Pharmaceutical Chemistry, University of Vienna, Vienna 1090, AustriaDepartment of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10903, ThailandStructural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandTargeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones <b>1c</b>, <b>2a</b>, <b>3e</b>, <b>4e</b>, and <b>4t</b> showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC<sub>50</sub> values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (<b>1c</b>, <b>2a</b> and <b>3e</b>) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.https://www.mdpi.com/1420-3049/24/6/1092chalcone derivativescytotoxicity assayEGFR tyrosine kinasemolecular dynamics simulationADMET |
| spellingShingle | Kanyani Sangpheak Lueacha Tabtimmai Supaphorn Seetaha Chompoonut Rungnim Warinthorn Chavasiri Peter Wolschann Kiattawee Choowongkomon Thanyada Rungrotmongkol Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors Molecules chalcone derivatives cytotoxicity assay EGFR tyrosine kinase molecular dynamics simulation ADMET |
| title | Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors |
| title_full | Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors |
| title_fullStr | Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors |
| title_full_unstemmed | Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors |
| title_short | Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors |
| title_sort | biological evaluation and molecular dynamics simulation of chalcone derivatives as epidermal growth factor tyrosine kinase inhibitors |
| topic | chalcone derivatives cytotoxicity assay EGFR tyrosine kinase molecular dynamics simulation ADMET |
| url | https://www.mdpi.com/1420-3049/24/6/1092 |
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