ArticleChemical science2021
Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Cell type-selective targeting by heterobifunctional protein binders via in-cell enrichment.Nature communications · 2026Article
- Thermodynamic Data Remain a Hot Tip for Decoding Binding Affinity and Water Impact on Protein-Ligand Complex Formation to Assist Lead Optimization.Journal of medicinal chemistry · 2026Review
- Novel PROTAC to target FKBP12: the potential to enhance bone morphogenetic protein activity and apoptosis in multiple myeloma.Haematologica · 2025Article
- High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein fromACS infectious diseases · 2024Article
- Automated Flow Peptide Synthesis Enables Engineering of Proteins with Stabilized Transient Binding Pockets.ACS central science · 2024Article
- Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins.Nature structural & molecular biology · 2023Article
- Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway.ACS pharmacology & translational science · 2023Review
- Article
- High concentrations of soluble endoglin can inhibit BMP9 signaling in non-endothelial cells.Scientific reports · 2023Article
- Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51.ACS pharmacology & translational science · 2023Review
- FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells.Cell communication and signaling : CCS · 2023Article
- SAFit2 reduces neuroinflammation and ameliorates nerve injury-induced neuropathic pain.Journal of neuroinflammation · 2022Article
- Binding pocket stabilization by high-throughput screening of yeast display libraries.Frontiers in molecular biosciences · 2022Article
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Authors and funding
18 authors.
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Abstract
Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.
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