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One ring to bind them all – the power of rings has captivated the fantasy community for decades. Now the research team of Professor Felix Hausch, Department of Chemistry at TU Darmstadt, has shown in two publications how in real life molecular rings worked the magic to improve compounds that could allow a new approach to treat depression, obesity or chronic pain.
In the Journal of Medicinal Chemistry ), the scientists published the macrocyclization of binding molecules for the FK506-binding protein 51. This protein is an important risk factor for diseases like depression, obesity and chronic pain. “However, identifying selectively binding molecules with drug-like properties has been the key challenge so far”, explains Prof. Felix Hausch from the Department of Chemistry. “Based on our structural insights into the binding mode of FKBP51 ligands we could design a macrocyclization approach, which alleviated key limitations of the previously available FKBP51 binders”.
In a landmark study supported by the Pioneer-Fund and the LOEWE consortium TRABITA and now published in the prestigious journal Angewandte Chemie International Edition, the Hausch lab went on to additionally identify a new macrocyclic class of FKBP51 binders, which for the first time were able to discriminate against the closely related homologs FKBP12 and FKBP12.6. “This could be key to avoid adverse side effect caused by FKBP12/12.6 inhibition”, says Professor Hausch.
Taken together, these two findings provide the key impetus towards the development of a clinical candidate for FKBP51 ready for testing in human patients. This is currently prosecuted within funding of the VIP+ grant Fit4Fat recently awarded to the Hausch lab. The methods of macrocyclization can also be applied to drug development for COVID19, as currently pursued in Pioneer Fund project CoMaProtInhib.
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors. In J. Med. Chem. 2021, 64, 6, 3320–3349, Publication Date: March 5, 2021.
DOI: https://doi.org/10.1021/acs.jmedchem.0c02195
Macrocyclic FKBP51 ligands define a transient binding mode with enhanced selectivity. In Angewandte Chemie, Publication Date: April 11, 2021.
DOI: https://doi.org/10.1002/anie.202017352
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