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Development and screening of chalcones against cancer protein targets using in silico and in vitro techniques |
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| รหัสดีโอไอ | |
| Title | Development and screening of chalcones against cancer protein targets using in silico and in vitro techniques |
| Creator | Kanyani Sangpheak |
| Contributor | Thanyada Rungrotmongkol, Chompoonut Rungnim |
| Publisher | Chulalongkorn University |
| Publication Year | 2561 |
| Keyword | Cancer -- Treatment, Cancer cells -- Growth -- Regulation, มะเร็ง -- การรักษา, เซลล์มะเร็ง -- การเจริญเติบโต -- การควบคุม |
| Abstract | Targeted cancer therapy has become one of high potential cancer treatments. Human topoisomerase IIα (hTopoIIα) and Epidermal growth factor receptor tyrosine kinase (EGFR-TK) are proteins that play important roles on cell cycle. The hTopoIIα catalyzes the cleavage and rejoining of double-stranded DNA while EGFR function on cell signaling. Thus, the two proteins have been suggested as molecular target for the development of novel cancer therapeutics. A series of 47 chalcone derivatives was screened against hTopoIIα and EGFR-TK by in silico and in vitro techniques. Chalcone 3d showed a high cytotoxicity with IC50 values of 10.8, 3.2 and 21.1 µM against the HT-1376, HeLa and MCF-7 cancer cell lines, respectively, while 1c, 2a, 3e, 4e and 4t exhibited potent compounds against A431 with IC50 values < 10 µM. To confirm the result the inhibition of those chalcone on enzyme assay was obtained. The 3d showed an inhibitory activity against hTopoIIα that was better than the known inhibitor, salvicine. Only three chalcones (1c, 2a and 3e) had an inhibitory activity against EGFR-TK with relative inhibition percentages closed to the approved drug, erlotinib. The binding interaction of potent chalcones complex with hTopoIIα and EGFR-TK were studied using molecular dynamics simulation. The observed 3d/hTopoIIα interactions affirmed that 3d strongly interacts with the ATP binding pocket residues while 1c, 2a and 3e/EGFR-TK were well occupied within the ATP binding site and strongly interacted with the 7 hydrophobic residues including the important hinge region residue M793. From ADMET properties, all six chalcones could be served as a lead compounds for development of hTopoIIα and EGFR-TK inhibitors. The information of drug development can be obtained by quantitative structure-activity relationship (QSAR) techniques. A series of chalcone derivatives against A431 were subjected to QSAR analyses. The MLR equation indicated a good correlation between observed and predicted values with R2 = 0.968. The understanding of the relationship between structures and pharmacological effects and the ligand-protein binding pattern leads to important information for the design of high potential anti-cancer drugs. |
| URL Website | cuir.car.chula.ac.th |
