Cover Image

In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells

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 pote...

Full description

Saved in:
Bibliographic Details
Main Authors: Abdulwahab, Muhammad Kumayl, Tan, Ke Han, Dzulkeflee, Rashidi, Leong, Kok Hoong, Heh, Choon Han, Ariffin, Azhar
Format: Article
Published: Elsevier 2021
Subjects:
QD Chemistry
R Medicine
Online Access:http://eprints.um.edu.my/25985/
https://doi.org/10.1016/j.molstruc.2020.129786
Tags: Add Tag
No Tags, Be the first to tag this record!
id my.um.eprints.25985
record_format eprints
spelling my.um.eprints.259852021-05-25T04:51:28Z http://eprints.um.edu.my/25985/ In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells Abdulwahab, Muhammad Kumayl Tan, Ke Han Dzulkeflee, Rashidi Leong, Kok Hoong Heh, Choon Han Ariffin, Azhar QD Chemistry R Medicine 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 Elsevier 2021 Article PeerReviewed 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 https://doi.org/10.1016/j.molstruc.2020.129786 doi:10.1016/j.molstruc.2020.129786
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic QD Chemistry
R Medicine
spellingShingle QD Chemistry
R Medicine
Abdulwahab, Muhammad Kumayl
Tan, Ke Han
Dzulkeflee, Rashidi
Leong, Kok Hoong
Heh, Choon Han
Ariffin, Azhar
In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
description 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
format Article
author Abdulwahab, Muhammad Kumayl
Tan, Ke Han
Dzulkeflee, Rashidi
Leong, Kok Hoong
Heh, Choon Han
Ariffin, Azhar
author_facet Abdulwahab, Muhammad Kumayl
Tan, Ke Han
Dzulkeflee, Rashidi
Leong, Kok Hoong
Heh, Choon Han
Ariffin, Azhar
author_sort Abdulwahab, Muhammad Kumayl
title In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
title_short In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
title_full In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
title_fullStr In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
title_full_unstemmed In-silico Studies of the Antiproliferative Activity of New Anilinoquinazoline Derivatives Against NSCLC Cells
title_sort in-silico studies of the antiproliferative activity of new anilinoquinazoline derivatives against nsclc cells
publisher Elsevier
publishDate 2021
url http://eprints.um.edu.my/25985/
https://doi.org/10.1016/j.molstruc.2020.129786
_version_ 1702170274413150208
score 13.211869

Similar Items