Fig. 7
From: Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation
Compound’s solution ensemble when in a reversible complex with KRASG13C, as observed in MD simulations. (A) and (B): fluctuation of the distance between Cys13 sulfur atom and the oxygen atom from the α-β-unsaturated carbonyl group is presented for each compound, while the respective distributions of these interatomic distances are indicated in the upper right graph for compounds 7a, 7b and 7d, representing compound with higher activity, and in the lower right graph for compounds 7f and 7i, representing compounds with lower activity (see population of conformers below 0.5 nm). The figures show that the less reactive compounds 7f and 7i adopt conformations of the warhead close to Cys13 far less often than compounds 7a, 7b, and 7c. C, KRASG13C in complex with ligand 7d presenting the warhead in a conformation within 4 Å to the sulfur atom from Cys13. The distance fluctuation (shown in dots) demonstrates that this interatomic distance is in equilibrium during simulation. Also, this ensemble is well reproduced in independent simulations (Figure S8).
