In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 3 ( 2023-3-9), p. e0282586-
Abstract:
A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an ( m -tolyl)acetamide theobromine derivative, ( T-1-MTA ). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA . Furthermore, ADMET analysis indicated the T-1-MTA ’s general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro . Intriguingly, T-1-MTA inhibited the EGFR protein with an IC 50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC 50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA ’s IC 50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0282586
DOI:
10.1371/journal.pone.0282586.g001
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10.1371/journal.pone.0282586.g002
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10.1371/journal.pone.0282586.g003
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10.1371/journal.pone.0282586.g004
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10.1371/journal.pone.0282586.g005
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10.1371/journal.pone.0282586.g006
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10.1371/journal.pone.0282586.g007
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10.1371/journal.pone.0282586.g008
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10.1371/journal.pone.0282586.g009
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10.1371/journal.pone.0282586.g010
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10.1371/journal.pone.0282586.g011
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10.1371/journal.pone.0282586.g012
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10.1371/journal.pone.0282586.g013
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10.1371/journal.pone.0282586.g014
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10.1371/journal.pone.0282586.g015
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10.1371/journal.pone.0282586.g016
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10.1371/journal.pone.0282586.g017
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10.1371/journal.pone.0282586.g018
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10.1371/journal.pone.0282586.g019
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10.1371/journal.pone.0282586.g020
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10.1371/journal.pone.0282586.g021
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10.1371/journal.pone.0282586.t001
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10.1371/journal.pone.0282586.t002
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10.1371/journal.pone.0282586.t003
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10.1371/journal.pone.0282586.t004
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10.1371/journal.pone.0282586.t005
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10.1371/journal.pone.0282586.t006
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10.1371/journal.pone.0282586.t007
DOI:
10.1371/journal.pone.0282586.s001
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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