In Silico and In Vitro Evaluations of Fluorophoric Thiazolo-[2,3-b]quinazolinones as Anti-cancer Agents Targeting EGFR-TKD.

Autor: Mir SA; School of Life Sciences, Sambalpur University, Jyoti Vihar, Burla, 768019, India., Dash GC; Department of Chemistry, APS College, Roth, Balangir, Odisha, 767061, India., Meher RK; Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, 768019, India., Mohanta PP; School of Chemistry, Sambalpur University, Jyoti Vihar, Burla, 768019, India., Chopdar KS; Department of Zoology, Rajendra College, Balangir, Odisha, 767002, India., Mohapatra PK; Department of Chemistry, C. V. Raman Global University, Bidyanagar, Mahura, Janla, Bhubaneswar, Odisha, 752054, India. pkmohapatra@cgu-odisha.ac.in., Baitharu I; Department of Environmental Sciences, Sambalpur University, Jyoti Vihar, Burla, 768019, India., Behera AK; School of Chemistry, Sambalpur University, Jyoti Vihar, Burla, 768019, India., Raval MK; School of Chemistry, Gangadhar Meher University, Sambalpur, Odisha, 768004, India. mraval@yahoo.com., Nayak B; School of Life Sciences, Sambalpur University, Jyoti Vihar, Burla, 768019, India. binata.bga@gmail.com.
Jazyk: angličtina
Zdroj: Applied biochemistry and biotechnology [Appl Biochem Biotechnol] 2022 Oct; Vol. 194 (10), pp. 4292-4318. Date of Electronic Publication: 2022 Apr 02.
DOI: 10.1007/s12010-022-03893-w
Abstrakt: Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a pivotal role in cellular signaling, growth, and metabolism. The EGFR-TKD is highly expressed in cancer cells and was endorsed as a therapeutic target for cancer management to overcome metastasis, cell proliferation, and angiogenesis. The novel thiazolo-[2,3-b]quinazolinones series were strategically developed by microwave-assisted organic synthesis and multi dominos reactions aimed to identify the potent thiazolo-[2,3-b]quinazolinone inhibitor against EGFR-TKD. This study explores the binding stability and binding strength of newly developed series via molecular docking, molecular dynamics simulation, and MM/PBSA and MM/GBSA calculations. The binding interaction was observed to be through the functional groups on aryl substituents at positions 3 and 5 of the thiazolo-[2, 3-b]quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions corroborating their bindings similar to the reference FDA-approved drug erlotinib in the active site. ADMET predictions reveal that derivatives 5ab, 5aq, and 5bq are drug-like and may be effective in in vitro study. Molecular dynamics simulation for 100 ns of docked complexes revealed their stability at the atomistic level. The ΔGbinding of thiazolo-[2,3-b]quinazolinone was found to be 5ab - 22.45, 5aq - 22.23, and 5bq - 20.76 similar to standard drug, and erlotinib - 24.11 kcal/mol was determined by MM/GBSA method. Furthermore, the anti-proliferative activity of leads of thiazolo-[2,3-b]quinazolinones (n = 3) was studied against breast cancer cell line (MCF-7) and non-small lung carcinoma cell line (H-1299). The highest inhibitions in cell proliferation were shown by 5bq derivatives, and the IC 50 was found to be 6.5 ± 0.67 µM against MCF-7 and 14.8 µM against H-1299. The noscapine was also taken as a positive control and showed IC 50 at higher concentrations 37 ± 1 against MCF-7 and 46.5 ± 1.2 against H-1299.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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