Results in Chemistry (Jan 2022)
Molecular dynamic simulation, free binding energy calculation of Thiazolo-[2,3-b]quinazolinone derivatives against EGFR-TKD and their anticancer activity
Abstract
Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a crucial role in the onset and progression of different types of cancers. The existing EGFR-TKD inhibitors have many adverse side effects, which make them unsuitable to be used as cancer therapeutics. This study aims to design novel molecular scaffolds that inhibit the EGFR-TKD with minimal side effects and further evaluate their suitability as an anti-cancer drug molecule using in vitro cell models. The binding energy of thiazolo-[2,3-b] quinazolinone derivatives against EGFR-TKD was determined using molecular docking and compared with positive control erlotinib (AQ44). Molecular docking demonstrated that higher bindings were exhibited by 1FTQ to 5 FTQ and the binding score ranged from −8.13 ± 0.0115 to −8.89 ± 0.0173 kcal/mol, which is higher than erlotinib −7.54 ± 0.1411 and noscapine −7.31 ± 0.5211 kcal/mol. Further, molecular dynamic simulations were performed to assess the stability of newly designed derivatives with EGFR-TKD. The stability of synthesized ligands was computed from the root mean square deviations. The enhanced free energy binding ΔGbind displayed by 4FTQ and 5FTQ was found to be −89.246 and −89.811 kJ/mol, which was comparable to the ΔGbind exhibited by erlotinib −130.595 kJ/mol, and a drastic decrease in free energy binding was shown by noscapine -25.98 kJ/mol. Moreover, the other synthetic congeners (1FTQ, 2FTQ, 3FTQ, 4FTQ, and 5FTQ) exhibited comparable free binding energy (ΔGbind), calculated by the MM-PBSA method. The anti-cancer activity of the compounds was assessed experimentally by a cell proliferation assay using Hep-G2 and MCF-7 cancer cell lines. Compound 3FTQ demonstrated the most potent anti-cancer activity against Hep-G2 with an IC50 value of 13.8 μM while compound 2FTQ showed promising anticancer activity against MCF-7 with an IC50 value of 21.1 μM. This study concluded that the compounds 1FTQ to 5FTQ may possess promising inhibitory activity against EGFR-TKD.
