期刊
COMPUTATIONAL BIOLOGY AND CHEMISTRY
卷 83, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.compbiolchem.2019.107156
关键词
Design; Pharmacophores; Docking; Synthesis; Chrysin derivatives; Cytotoxicity; Mammosphere forming ability
资金
- Department of Biotechnology (DBT), New Delhi, Government of India [6242-P65/RGCB/PMD/DBT/AMTD/2015]
- DBT-SRF
- CSIR-SRF
- DBT [BT/327/NE/TBP/2012]
Background & objective: Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity. Methods: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score >= 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using H-1-NMR, C-13-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin. Results: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells. Conclusion: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.
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