Identification of potent epidermal growth factor receptor (EGFR) inhibitors as potential lung cancer medications via virtual screening of 1,2,3-triazole containing pyridineamide derivatives

Abstract

The challenges of non-specific targeting, drug resistance, and intrinsic toxicities that characterize virtually all chemotherapeutic agents against lung cancer have made the need to constantly search for newer and better alternatives very necessary. In this study, some bioactive 1,2,3-triazole containing pyridineamide derivatives with proven in vitro anti-proliferative activities against lung cancer cells were screened against human EGFR, a prominent molecular target in lung cancer treatment. The promising ligands identified were further subjected to ADMET profiling and DFT calculations to assess their pharmacokinetic properties and electronic features. The results of molecular docking based virtually screening revealed that the more promising bioactive molecules bind spontaneously to the active sites of EGFR with average docking score (∆G m ) that ranges from -9.5 to -10.5 kcal/mol while the standard EGFR antagonists; gefitinib and erlotinib bind to the target macromolecule with ∆G values of -8.4 and -7.1 kcal/mol, respectively. Also, DFT calculations on two of the most promising ligands (MPLs); 6 and 14 revealed LUMO-HOMO energy gaps of 4.15 and 4.48 eV, respectively, and these values are comparable with the 4.29 and 4.3 eV computed for erlotinib and gefitinib, respectively. Additionally, in silico ADMET profiling revealed that the MPLs are expected to have better pharmacokinetics and toxicity profiles than the control drugs and as such could be novel sources of medications for lung cancer treatment.