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Biological evaluation and molecular dynamics simulation of chalcone derivatives as epidermal growth factor-tyrosine kinase inhibitors
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Document Title
Biological evaluation and molecular dynamics simulation of chalcone derivatives as epidermal growth factor-tyrosine kinase inhibitors
Author
Sangpheak K., Tabtimmai L., Seetaha S., Rungnim C., Chavasiri W., Wolschann P., Choowongkomon K., Rungrotmongkol T.
Name from Authors Collection
Affiliations
Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand; Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10903, Thailand; National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand; Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, 1090, Austria; Institute of Theoretical Chemistry, University of Vienna, Vienna, 1090, Austria; Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand; Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
Type
Article
Source Title
Molecules
ISSN
14203049
Year
2019
Volume
24
Issue
6
Open Access
Gold, Green
Publisher
MDPI AG
DOI
10.3390/molecules24061092
Abstract
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 1c, 2a, 3e, 4e, and 4t showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC50 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 (1c, 2a and 3e) 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. © 2019 by the authors.
Funding Sponsor
Thailand Research Fund; Thailand Graduate Institute of Science and Technology
License
CC BY
Rights
Author
Publication Source
Scopus