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

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Small molecules targeting Son of Sevenless 1 (SOS1) aim to inhibit RAS activation for antitumor effects.
• Existing SOS1 inhibitors face challenges in achieving high affinity and potency.

Purpose of the Study:

• To identify novel strategies for enhancing the affinity of small molecule SOS1 inhibitors.
• To explore the potential of targeting solvent-exposed acidic residues for improved drug design.

Main Methods:

• Free-energy perturbation (FEP+) simulations were employed to guide inhibitor design.
• Structure-Activity Relationship (SAR) studies were conducted to validate computational findings.
• X-ray crystallography was used to elucidate the binding interactions at the molecular level.

Main Results:

• Two acidic residues (E906, E909) on SOS1 were identified as a key 'potency handle'.
• Targeting these residues with basic groups resulted in up to a 750-fold increase in inhibitor affinity.
• Electrostatic interactions, specifically salt bridges, were confirmed as the mechanism for affinity enhancement.

Conclusions:

• The electrostatic interaction with solvent-exposed acidic residues represents a generalizable strategy for developing potent SOS1 inhibitors.
• This approach can be repurposed for broader drug discovery efforts targeting other protein classes.
• The findings provide a new avenue for the development of targeted cancer therapies.