Abdulwahab, Muhammad Kumayl and Tan, Ke Han and Dzulkeflee, Rashidi and Leong, Kok Hoong and Heh, Choon Han and Ariffin, Azhar (2021) In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells. Journal of Molecular Structure, 1228. p. 129786. ISSN 0022-2860, DOI https://doi.org/10.1016/j.molstruc.2020.129786.
Full text not available from this repository.Abstract
The current reversible epidermal growth factor (EGFR) tyrosine kinase inhibitors of non-small cell lung cancer (NSCLC) have been resisted by T790M mutation, while the irreversible inhibitors introduced to overcome the mutation have faced resistance from C979S mutation. In the effort to discover potentially improved reversible EGFR inhibitors, a series of new anilinoquinazoline derivatives with modification on the 2nd carbon on the aniline ring was synthesized. The derivatives were tested for their antiproliferative activity against NSCLC cell lines with wild-type (A549), exon 19 deletion mutated (H1650) and L858R+T790M (H1975) mutated EGFR kinases. Three derivatives (4-6) performed better than the standard drug, gefitinib, in all cell lines. Derivative 5 recorded the lowest IC50 values in all cell lines (A549: 24.60 ± 0.75 µM, H1650: 14.83 ± 0.54 µM, H1975: 21.72 ± 1.21 µM). A molecular docking study followed by molecular dynamics simulations was performed on derivative 5 and gefitinib using wild-type EGFR kinase (WT-EGFR) and L858R+T790M mutated kinase (LRTM-EGFR) to provide an understanding of their binding mechanisms. In WT-EGFR kinase, derivative 5 recorded better hydrogen bonding occupancy with MET793 (94.16%) and binding energy profile (-35.287 kcal/mol) as compared to gefitinib (91.80%, -26.071 kcal/mol). In LRTM-EGFR kinase, derivative 5 recorded better hydrogen bonding occupancy with MET793 (93.68%) as compared to gefitinib (91.48%). Derivative 5 also recorded additional hydrogen bonding interactions with ASP855, with a total of 60.61% occupancy as well as a better energy profile (-42.867 kcal/mol) as compared to gefitinib (-41.778 kcal/mol). © 2020
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Higher Education, Fundamental Research Grant (FRGS/1/2019/SKK09/UM02/1), University of Malaya Research Programme (RP035-17AFR) |
| Uncontrolled Keywords: | EGFR kinase inhibitor; anilinoquinazoline; synthesis; antiproliferative activity; molecular docking; molecular dynamics |
| Subjects: | Q Science > QD Chemistry R Medicine |
| Divisions: | Faculty of Medicine Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 25 May 2021 04:51 |
| Last Modified: | 25 May 2021 04:51 |
| URI: | http://eprints.um.edu.my/id/eprint/25985 |
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