ArticleACS medicinal chemistry letters2025
Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.
Article in ACS medicinal chemistry letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The trial behind it
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Who cites it
5 citing papers in PubMed.
- Synthesis and Biochemical Characterization of Investigational Pyrazolopyrimidine-Based Allosteric KRAS Modulators.ACS medicinal chemistry letters · 2026Article
- SOS1: tracking the evolving path from promising to actionable therapeutic target in RAS-dependent cancers.Molecular cancer · 2026Review
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Focused Structure-Based Virtual Screening Identifies Novel Inhibitors of SOS1.ACS medicinal chemistry letters · 2025Article
- Identification of Novel 2‑(Azetidin-3-ylamino)-nicotinamide Derivatives as Potent KRAS::SOS1 Inhibitors.ACS medicinal chemistry letters · 2025Article
Corrections and comments
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
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 antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906 and E909, 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. Additional recent examples in the literature suggest that this phenomenon may be applicable to a number of target classes and are highlighted herein.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.