Summary for 9MJM
| Entry DOI | 10.2210/pdb9mjm/pdb |
| Descriptor | Son of sevenless homolog 1, 2-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-3-(2-oxaspiro[3.3]heptan-6-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | oncology, exchange factor, protein-ligand complex, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 57993.26 |
| Authors | |
| Primary citation | Leffler, A.E.,Houang, E.M.,Gray, F.,Placzek, A.T.,Ruvinsky, A.M.,Bell, J.A.,Wang, H.,Sun, S.,Svensson, M.,Greenwood, J.R.,Frye, L.L.,Igawa, H.,Atsriku, C.,Levinson, A.M. Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations. Acs Med.Chem.Lett., 16:444-453, 2025 Cited by PubMed 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. PubMed: 40104782DOI: 10.1021/acsmedchemlett.4c00602 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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