Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles
Macrocycles are promising drug modalities that can enable unique ways of conformational preorganization, but how even minor modifications to a macrocyclic scaffold influence the conformational preorganization remains poorly understood. Here, we show how macrocyclization and further derivatization of the linker region can improve affinity, selectivity, and plasma stability in a highly atom-efficient manner. A single, solvent-exposed methyl group was found to improve binding affinity up to 10× over the nonmethylated analog. This led to highly ligand-efficient macrocycles with good brain permeability, improved solubility, and a promising in vivo profile for the FK506-binding protein 51 (FKBP51), a key regulator of the human stress response. Using high-resolution cocrystal structures and molecular dynamics simulations, we found that small linker variations can be tuned to shift the orientation of a key carbonyl group into an advantageous position. This effect is specific to macrocycles, highlighting their potential for fine-tuned adjustments to enable desired properties.
Authors
- Enrico Ruijsenaars
- Patricia Muschong
- Sereina Riniker (ORCID: https://orcid.org/0000-0003-1893-4031)
- Wisely Oki Sugiarto
- Mario Mezler (ORCID: https://orcid.org/0000-0002-7253-0962)
- Mathias V. Schmidt (ORCID: https://orcid.org/0000-0002-3788-2268)
- Felix Hausch (ORCID: https://orcid.org/0000-0002-3710-8838)
- Christian Meyners (ORCID: https://orcid.org/0000-0002-1960-6833)
- Vanessa Buffa (ORCID: https://orcid.org/0000-0002-7440-6949)
- Undine Haferkamp (ORCID: https://orcid.org/0000-0003-2893-5847)
- Margherita Springer (ORCID: https://orcid.org/0000-0002-2361-4940)
- Ole Pleß (ORCID: https://orcid.org/0000-0002-1468-316X)
- Arjen Weller
- Maximilian Repity
- Christian Brudy
- Moritz Spiske (ORCID: https://orcid.org/0009-0002-2906-2398)
- Hanaa Achaq
- Dominik Miltner
Institutions
- AbbVie (United States) (US)
- Technische Universität Darmstadt (DE)
- ETH Zurich (CH)
- Quantitative BioSciences (US)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- AbbVie (Germany) (DE)
- Max Planck Institute of Psychiatry (DE)
- Institute of Neurobiology (BG)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00958
- Citations
- 1
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81