Furopyridine Derivatives\nas Potent Inhibitors of the\nWild Type, L858R/T790M, and L858R/T790M/C797S EGFR

The\ntreatment of patients with nonsmall cell lung cancer (NSCLC)\nusing epidermal growth factor receptor (EGFR) inhibitors is complicated\nby drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations.\nTo overcome drug resistance, a series of furopyridine (PD) compounds\nwere virtually screened to identify potent EGFR inhibitors using molecular\ndocking and molecular dynamics (MD) simulations based on the solvated\ninteraction energy (SIE) method. Several PD compounds identified from\nvirtual screening demonstrated the potential to suppress both wild-type\nand mutant forms of EGFR, with IC<sub>50</sub> values in the nanomolar\nrange. Among these, <b>PD18</b> and <b>PD56</b> exhibited\nhighly potent inhibitory activity against both wild-type and mutant\nforms of EGFR, surpassing the efficacy of known drugs. Additionally,\nboth PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975)\nwhile being nontoxic to normal cell lines (Vero). The interaction\nmechanisms of both PD compounds complexed with wild-type and mutant\nforms of EGFR were elucidated through 500 ns molecular dynamics simulations.\nThe predicted binding affinity from molecular mechanics/Poisson–Boltzmann\nsurface area (MM/PBSA) correlated well with the experimental binding\naffinity derived from IC<sub>50</sub> values. Furthermore, it was\nobserved that van der Waals interactions, rather than electrostatic\ninteractions, played a significant role in interacting with EGFR’s\nactive site. The strong inhibitory activity against EGFR was attributed\nto two key residues, M793 and S797, via hydrogen bonding, corresponding\nwith lower solvent accessibility and a higher number of atomic contacts.\nTherefore, these potent compounds could be developed as promising\ndrugs targeting both wild-type and mutant EGFR for the treatment of\nNSCLC.