Applied Pharmaceutical Chemistry 2025

Exploiting Solvent-Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free Energy Perturbation Simulations

Speaker:
Abba Leffler, Senior Principal Scientist, Schrödinger

Abstract:
Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and anti-tumor activity. Guided by free energy perturbation simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906, and 909, constitute a potency handle that can improve inhibitor affinity by as much as 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure-activity relationship (SAR) and X-ray crystallographic studies demonstrate that this effect is attributable to the electrostatic interaction between the protein and ligand. This interaction could be repurposed to create new SOS1 inhibitors, documenting its general utility for core exploration. This short talk will focus on these SAR efforts and also provide recent examples in the literature that suggest that this phenomenon may be applicable to a number of target classes.