Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

Molecules

Warinthorn Chavasiri¹  Supaphorn Seetaha²  Lueacha Tabtimmai²  Kiattawee Choowongkomon²  Peter Wolschann³  Chompoonut Rungnim⁴  Kanyani Sangpheak⁵  Thanyada Rungrotmongkol⁶ 

[1] Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10903, Thailand;Department of Pharmaceutical Chemistry, University of Vienna, Vienna 1090, Austria;National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand;Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;

关键词: chalcone derivatives;    cytotoxicity assay;    EGFR tyrosine kinase;    molecular dynamics simulation;    ADMET;   

DOI  :  10.3390/molecules24061092

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown