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

Kolos, J. M., Pomplun, S., Jung, S., Riess, B., Purder, P. L., Voll, A. M., et al. (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. doi:10.1039/d1sc04638a.

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 Creators:
Kolos, Juergen M.1, Author
Pomplun, Sebastian1, Author
Jung, Sascha1, Author
Riess, Benedikt1, Author
Purder, Patrick L.1, Author
Voll, Andreas M.1, Author
Merz, Stephanie1, Author
Gnatzy, Monika1, Author
Geiger, Thomas M.1, Author
Quist-Lokken, Ingrid1, Author
Jatzlau, Jerome1, Author
Knaus, Petra1, Author
Holien, Toril1, Author
Bracher, Andreas2, Author              
Meyners, Christian1, Author
Czodrowski, Paul1, Author
Krewald, Vera1, Author
Hausch, Felix1, Author
Affiliations:
1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: RATIONAL DESIGN; PROTEIN; BINDING; DISCOVERY; LIGANDS; IMPACT; POTENTChemistry;
 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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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000714011000001
DOI: 10.1039/d1sc04638a
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Title: Chemical Science
  Other : Chem. Sci.
Source Genre: Journal
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Publ. Info: Cambridge, UK : Royal Society of Chemistry
Pages: - Volume / Issue: 12 (44) Sequence Number: - Start / End Page: 14758 - 14765 Identifier: ISSN: 2041-6520
CoNE: https://pure.mpg.de/cone/journals/resource/2041-6520