In-Silico Evaluation, Chemical Reactivity, and Covalent Docking Study of Various Quinazolines and Pyridopyrimidines as Inhibitors for the Epidermal Growth Factor Receptor

Abstract

The epidermal growth factor receptor (EGFR) sensitivity to tyrosine kinase inhibitors gefitinib and erlotinib-activated mutants is common in non-small cell lung cancer. An in-silico screening study of quinazolines and pyridopyrimidines against the wild-type (WT) and mutation of EGFR tyrosine kinase inhibitors was conducted, employing several computational approaches such as covalent docking and molecular dynamics simulation followed by reactivity and the absorption, distribution, metabolism, excretion, and toxicity (ADMET). Twenty-two heterocyclic compounds were screened by covalent docking against WT and mutated proteins (L858R and T790M). Compounds 4 and 19, which contain quinazoline[3,4-d]pyrimidine and pyrido[3,4-d]pyrimidine, respectively, were found to have an affinity toward the wild-type and the mutant protein. In addition, they had good chemical reactivity and kinetic stability toward the WT and mutations and desirable ADMET properties. These findings reveal new, robust, and irreversible tyrosine kinase inhibitors for the WT and its mutant proteins.

Graphical Abstract

Keywords:

• ADMET
• EGFR
• tyrosine kinase family
• covalent docking
• molecular dynamic simulation and reactivity

Acknowledgments

H. Khelfaoui and D. Harkati thank the University of Biskra and B.A. Saleh thanks the University of Basrah for their support. G.A. El-Hiti acknowledges the support received from Researchers Supporting Project (number RSP2023R404), King Saud University, Riyadh, Saudi Arabia. Molecular dynamics simulations were performed using facilities provided by the University of Cape Town’s ICTS High-Performance Computing team.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by King Saud University [RSP2023R404].