In silico design of EGFRL858R/T790M/C797S inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations

Abstract

The development of L858R/T790M/C797S mutations in EGFR is one of the main reasons for the emergence of resistance after third-generation treatment of non-small cell lung cancer (NSCLC). Therefore, the development of 4th generation drugs needs urgent attention. To overcome resistance, in silico drug discovery and Design approaches were employed on a library of 29 novel 9-heterocyclyl substituted 9H-purines derivatives with EGFRL858R/T790M/C797S inhibition for anticancer activity against NSCLC. The COMSIA/EHA model (Q2 = 0.584, R2 = 0.816, and Rpred2 = 0.73) showed a stable and reliable predictive ability of NSCLC activity, which was tested by several validation methods. Molecular docking studies reveal crucial interactions with EGFRL858R/T790M/C797S inhibition for NSCLC activity. Based on theoretical methods, we designed 10 new compounds with good activity potential, which were tested using ADMET properties. Next, the molecular docking results were examined by molecular dynamics simulations to verify the stability of hydrogen bonding interactions with important residues such as MET790, MET793 and SER797, which are essential for the design of 4th generation EGFR Inhibitors to combat drug-resistant NSCLC.