Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases

Altaf Ahmad Shah; Nitish Kumar; Preet Mohinder Singh Bedi; Salman Akhtar

doi:10.1080/07391102.2023.2274974

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFR^wt and mutant EGFR^T790M receptor tyrosine kinases

J Biomol Struct Dyn. 2023 Nov 3:1-23. doi: 10.1080/07391102.2023.2274974. Online ahead of print.

Authors

Altaf Ahmad Shah¹, Nitish Kumar², Preet Mohinder Singh Bedi², Salman Akhtar^{3

4}

Affiliations

¹ Department of Biosciences, Integral University, Lucknow, India.
² Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
³ Department of Bioengineering, Integral University, Lucknow, India.
⁴ Novel Global Community Educational Foundation, Hebersham, Australia.

PMID: 37921704
DOI: 10.1080/07391102.2023.2274974

Abstract

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFR^wt inhibition and QU351, for EGFR^mt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

Keywords: Tumor-angiogenesis; cardiotoxicity; epidermal growth factor receptor; kinase domain; metabolic reactivity; molecular docking; molecular dynamics simulation; quinazolines.