Fig. 8: Structural model of EGFR–BI4020 interactions.
From: A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer
a The binding mode of BI-4020 for the EGFR-L858R/T790M/C797S/L718M mutant. EGFR was depicted by a surface model (M718, cyan; M790, red; S797, yellow; R858, orange; others, gray), and BI-4020 was depicted by sticks (C, green; N, blue; and O, red). An enlarged view of the ATP-binding pocket is shown in the right panel. b Hydrogen bonds between the EGFR-L858R/T790M/C797S/L718M mutant and BI-4020. The protein backbone is represented by a ribbon diagram, and the side chains (K745, M793, and T854) and BI-4020 are depicted as sticks. Hydrogen bonds are shown as dashed yellow lines. c Binding free energies (ΔG) of BI-4020 toward the L747P, L858R/T790M/C797S, and L858R/T790M/C797S/L718M mutants. Electrostatic (Coulomb) and van der Waals (vdW) contributions to the ΔG values are also indicated. The binding affinity for the L747P mutant is significantly lower than that for the L858R/T790M/C797S or L858R/T790M/C797S/L718M mutant owing to the loss of vdW interactions. d Structural comparison of the L747P, L858R/T790M/C797S, and L858R/T790M/C797S/L718M mutants. Orientational changes in the phosphate-binding loop (P-loop) and αC-helix upon the L747P mutation are indicated by blue arrows. In a–d, the energetically stable structure of the EGFR–BI-4020 complex was extracted from five independent 100 ns molecular dynamic simulations.
