In silico target specific design of potential quinazoline-based anti-NSCLC agents

Abstract

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In spite of great advances, treatment of the disease is a medical challenge. Epidermal-growth factor receptor (EGFR) has been taken as a promising cell surface target to develop anti-NSCLC therapies. The main bottleneck to attain clinical efficacy with current EGFR tyrosine kinase inhibitors (EGFR-TKIs) is the rapid spread of oncogenic mutations. Numerous efforts have been made for the synthesis of diverse EGFR-TKIs against resistance-conferring mutations. One of the best strategies to design potent agents would be to explore existing anti-NSCLC drugs at the nonclinical development stage and prioritize privileged structural patterns. Within current study, conformational stability of clinically frequent EGFR mutants (G719S, T790M, L858R and a double mutant form L858R/T790M) were validated via DynaMut and missense3D computational servers. Subsequently, structure activity relationship (SAR) and scaffold similarity inquiry were used to rationally propose a few erlotinib analogues. Intended molecules were subjected to molecular docking and top-scored binders were further analyzed through 50-ns all atom molecular dynamics (MD) simulations to infer the dynamic behavior. The aim was to offer potential binders to overwhelm clinically frequent EGFR-TK mutants. The linear interaction energy (LIE) method was applied to compute the binding free energies between EGFR and intended ligands. For this purpose, MD-based conformational sampling of ligand-enzyme complexes and ligand-water associations were used to acquire thermodynamic energy averages. Though mechanistic details are to be explored, results of the current study identify synthetically accessible quinazoline small molecules with potential affinity toward frequent EGFR-TK mutants.

Communicated by Ramaswamy H. Sarma

HIGHLIGHTS

• Consecutive in silico procedure on a few rationally designed erlotinib analogues introduced two molecules with high theoretical affinity to clinically frequet mutant EGFRs (6a and 22a).

• MD simulations of top-ranked docked molecules were indicative of tight packed complexes and showed that mutant EGFR backbones were stable upon binding to probable inhibitors.

• The results of LIE method confirmed binding patterns of intended ligands and showed the dominance of van der Waals over electrostatic interactions in ligand-enzyme complexes.

• In overall it might be deduced that central quinazoline ring had more binding contributions toward EGFR active site in 22a.

• Regarding SASA distribution patterns, it might be inferred that the simulation time of 50 ns could screen equilibrated complex systems.

Keywords:

• NSCLC
• Erlotinib
• SAR
• Binding
• Molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Ardabil University of Medical Sciences under Grant IR.ARUMS.REC.1399.441.