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Kolos JM, Pomplun S, Jung S, et al. Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides. Chem Sci. 2021;12(44):14758-14765doi: 10.1039/d1sc04638a.
Kolos, J. M., Pomplun, S., Jung, S., Rieß, B., Purder, P. L., Voll, A. M., Merz, S., Gnatzy, M., Geiger, T. M., Quist-Løkken, I., Jatzlau, J., Knaus, P., Holien, T., Bracher, A., Meyners, C., Czodrowski, P., Krewald, V., & Hausch, F. (2021). Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides. Chemical science, 12(44), 14758-14765. https://doi.org/10.1039/d1sc04638a
Kolos, Jürgen M, et al. "Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides." Chemical science vol. 12,44 (2021): 14758-14765. doi: https://doi.org/10.1039/d1sc04638a
Kolos JM, Pomplun S, Jung S, Rieß B, Purder PL, Voll AM, Merz S, Gnatzy M, Geiger TM, Quist-Løkken I, Jatzlau J, Knaus P, Holien T, Bracher A, Meyners C, Czodrowski P, Krewald V, Hausch F. Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides. Chem Sci. 2021 Nov 03;12(44):14758-14765. doi: 10.1039/d1sc04638a. eCollection 2021 Nov 17. PMID: 34820091; PMCID: PMC8597852.
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Chem Sci. 2021 Nov 03;12(44):14758-14765. doi: 10.1039/d1sc04638a. eCollection 2021 Nov 17.

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.

Chemical science

Jürgen M Kolos, Sebastian Pomplun, Sascha Jung, Benedikt Rieß, Patrick L Purder, Andreas M Voll, Stephanie Merz, Monika Gnatzy, Thomas M Geiger, Ingrid Quist-Løkken, Jerome Jatzlau, Petra Knaus, Toril Holien, Andreas Bracher, Christian Meyners, Paul Czodrowski, Vera Krewald, Felix Hausch

Affiliations

  1. Department of Chemistry, Technical University of Darmstadt Alarich-Weiss-Straße 4 64293 Darmstadt Germany [email protected].
  2. Max Planck Institute of Psychiatry Kraepelinstr. 2-10 80804 München Germany.
  3. Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie Otto-Hahn-Straße 6 44227 Dortmund Germany.
  4. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology 7491 Trondheim Norway.
  5. Department of Immunology and Transfusion Medicine, St. Olav's University Hospital 7030 Trondheim Norway.
  6. Department of Hematology, St. Olav's University Hospital 7030 Trondheim Norway.
  7. Institute for Chemistry and Biochemistry, Freie Universität Berlin 14195 Berlin Germany.
  8. Research Department Cellular Biochemistry, Max Planck Institute of Biochemistry Am Klopferspitz 18, 82152 Planegg Germany.

PMID: 34820091 PMCID: PMC8597852 DOI: 10.1039/d1sc04638a

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.

This journal is © The Royal Society of Chemistry.

Conflict of interest statement

There are no conflicts to declare.

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