Computational identification of new TKI as potential noncovalent reversible EGFRL858R/T790M inhibitors: VHTS, molecular docking, DFT study and molecular dynamic simulation

Abstract

The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. In this study, we employed a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 50.000 Erlotinib-derived compounds as noncovalent reversible EGFRL858R/T790M inhibitors. Our HTVS work flow leverages include HTVS, SP (Standard Precision) and XP (Extra Precision) docking protocol along with its relative binding free energy calculation, cluster analysis study and ADMET properties. Then we used multiple ns-time scale molecular dynamics (MD) simulations and density functional theory (DFT) precise calculation techniques to elucidate how the bound ligand interact with the complexes conformational states involving motions both proximal and distal to the binding site. Based on glide score and protein–ligand interactions, the highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. A hyperfine analysis of DFT based refinement strategy highly supported their stability by strong intermolecular interactions. Together, our results demonstrate that the virtually screened top retained molecules present the best moieties introduced to Erlotinib. They exhibit interesting pharmacokinetic properties that can act as potent antitumor drug candidates than the lead compound drug and in some extent tackling the drug resistance problem which offer a springboard for further therapeutic experiments and applications. Communicated by Ramaswamy H. Sarma