Fig. 6: Estimation of the stability of Rasarfin and compound 21.4 binding modes.

a Root Mean Square Deviation (RMSD) (y axis) for Rasarfin (orange) and 21.4 (red) in respect to their initial position were analyzed in three separate MD runs. RMSD values higher than 6 correspond to simulation frames in which the ligand fully unbinds. The ligand position was monitored across 3 separate replicates of 4 μs (total 12 μs). b Comparison of predicted binding mode of Rasarfin (orange licorice) and compound 21.4 (red licorice). The molecular surface of Ras is represented in white and reveals the presence of a structural cavity in the vicinity of the predicted binding modes (black circle). In the predicted binding mode of Rasarfin, the structural cavity is occupied by the chlorine atom (in green), which is missing in compound 21.4. c Overlay of Rasarfin binding into the Ras-SOS binding interface (PDB:1BKD). Rasarfin is displayed in orange licorice, SOS in yellow, and Ras in red ribbons. The surface occupied by Rasarfin is shown in transparent gray. Residues on Ras and SOS are highlighted in respective colors and labeled accordingly. Rasarfin is binding in the cavity which is normally occupied by residues His911 and Lys939 of SOS. Those residues are shown superimposed with Rasarfin, displaying His911 overlaying with the furan of the benzofuran moiety (AR1), and the Lysine elongated in the binding groove like Rasarfin, partially hidden as they overlay perfectly.