Molecular Rings with Drug-like Properties

Chemistry team of the TU publishes new drug discovery approaches

2025/02/04

Ring-shaped molecules often have better pharmacological properties, but the development of these active substances is difficult. Now the working group led by Professor Felix Hausch at the Clemens Schöpf Institute for Organic Chemistry and Biochemistry at TU Darmstadt has shown in three publications how molecular rings can be built using a modular assembly and how this translates to better properties. This opens up new approaches, for example for the treatment of depression, obesity or chronic pain.

In two articles in the renowned journal Angewandte Chemie, the research team described methods how macrocycles can be quickly assembled and decorated. “The tailor-made introduction of side chains has so far been an unsolved problem,” explain Vanessa Buffa and Carlo Walz, lead authors of the first paper. “By specifically producing precursor building blocks, we were able to systematically investigate the linker region in macrocycles for the first time. This enabled us to thus substantially improve the pharmacological properties.” “Through extensive structural analysis, we were able to see the full picture of the mobility of macrocycles for the first time,” adds Moritz Spiske, lead author of the second paper. These studies represent a breakthrough towards better drugs for the FK506-binding protein 51, which is an important risk factor for diseases such as depression, obesity and chronic pain.

Makrozyklen wie hier als Kugel-Stab-Modell (im Komplex mit dem Protein FKBP51, PDB-ID 9GQG) können hoch effiziente Wirkstoffe ermöglichen, aber es ist schwer, die richtigen Makrozyklen zu finden. Die build-pair-couple-Strategie von Spiske et al. bzw. Buffa und Walz et al. erlauben das schnelle Zusammensetzen von divers dekorierten Makrozyklen, speziell im Linker-Bereich (als blaue Stäbe gezeigt). Die entscheidenden Seitenketten-Modifikationen sind als rote Kugeln hervorgehoben. — Macrocycles like the one depicted in a rod-sphere representation (in complex with the protein FKBP51 shown as grey surface, PDB-ID: 9GQG) can enable powerful drugs but their exploration has been difficult. The build-pair-couple strategy by Spiske et al. and Buffa and Walz et al. allow the rapid assembly of diversely decorated macrocycles, especially in the linker part (shown as blue rods). The key side chain modification highlighted as red spheres.

In another publication in the Journal of Medicinal Chemistry, Carlo Walz and Moritz Spiske, in collaboration with the pharmaceutical company Abbvie, were able to show that ring closure in macrocycles systematically leads to an improvement in aqueous solubility. “This makes it easier to administer the active ingredients, which is especially problematic for difficult drug targets” explains Professor Hausch. This work builds on key findings of the Pioneer Fund project CoMaProtInhib, was funded by the VIP+ project Fit4Fat and the DFG project BrainMC, and is now being continued in the EU consortium MC4DD.

Hausch/mih

The publications

Conformationally Restricted Macrocycles as Improved FKBP51 Inhibitors Enabled by Systematic Linker Derivatization: https://doi.org/10.1002/anie.202418511

Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles: https://doi.org/10.1002/anie.202418512

Macrocyclization as a Strategy for Kinetic Solubility Improvement: A Comparative Analysis of Matched Molecular Pairs