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. 2022 May 1;23(5):1687-1697.
doi: 10.31557/APJCP.2022.23.5.1687.

Identification of oxazolo[4,5-g]quinazolin-2(1H)-one Derivatives as EGFR Inhibitors for Cancer Prevention

Renganthan Senthil  1 , Kishore Kumar Meenakshi Sundaram  2 , Giridharan Bupesh  3 , Singaravelu Usha  4 , Konda Mani Saravanan  2
Affiliations

Identification of oxazolo[4,5-g]quinazolin-2(1H)-one Derivatives as EGFR Inhibitors for Cancer Prevention

Renganthan Senthil et al. Asian Pac J Cancer Prev. .

Abstract

Objective: Abnormal expression of EGFR (epidermal growth factor receptor) results in different types of human tumors. Quinazoline-containing derivative signify an attractive platform for EGFR inhibitors. The present study aims to discover the potential binders of a group of compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative as EGFR inhibitors.

Methods: We apply multiple computational procedures, including pharmacophore-based virtual screening methods, to perform a preliminary screening against EGFR over compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative. Then, we carried a fine screening by molecular dynamics simulations, followed by free energy calculations.

Results: The best pharmacophore model created has five characteristics. Three hydrogen bonds acceptors (A) and two aromatic rings (R) make up AAARR (a sequential representation of chemical features of ligands). We have performed pharmacophore-based screening with different databases like Asinex, Chembridge, Lifechemicals, Maybridge, Specs, and Zinc. Top-scoring 30 molecules were considered for performing induced fit docking. Molecular Dynamics Simulations executed for the top five ligands confirmed that throughout the simulation, the protein-ligand complexes remained stable.

Conclusion: Thus, the results obtained from this research provide insights for the development of oxazolo[4,5-g]quinazoline-2(1H)-one derivative as potent EGFR inhibitors.

Keywords: Tyrosine kinase; cancer biology; drug discovery; inhibitor discovery; pharmacophore-based virtual screening.

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Figures

Figure 1
Figure 1
(a). Generation of a pharmacophore hypothesis based on properties of potent 24 oxazolo [4, 5-g] quinazolin-2(1H)-one derivatives as EGFR kinase inhibitors. (b). Intersite distance of the pharmacophore model
Figure 2
Figure 2
Molecular Electrostatic Profiles of Compounds. (a), ZINC06483405; (b), ZINC14436570; (c), F2565-0145; (d), ZINC03861279; (e), ZINC01031908
Figure 3
Figure 3
HOMO and LUMO of Compounds (a). ZINC06483405, (b). ZINC14436570, (c). F2565-0145, (d). ZINC03861279 and (e). ZINC01031908
Figure 4
Figure 4
(a). RMSD and (b). RMSF graph of the top five compounds with EGFR
Figure 5
Figure 5
Protein-Ligand Interactions of the Compounds (a), ZINC06483405; (b), ZINC14436570; (c), F2565-0145; (d), ZINC03861279; (e), ZINC01031908with EGFR (PDB: 4I22) before and after dynamics
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