Wirth, Ulrike and Neu, Eduard and Provasi, Davide and Feustel, Steffen and Schmidt, Maximilian F. and Huebner, Harald and Weikert, Dorothee and Filizola, Marta and Koenig, Burkhard and Gmeiner, Peter (2025) Synthesis and Characterization of Photoswitchable Covalent Ligands for the β2-Adrenoceptor. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 64 (24): e202424038. ISSN 1521-3773
Full text not available from this repository. (Request a copy)Abstract
The beta 2-adrenergic receptor (beta 2AR) is a critical target for the treatment of airway diseases such as asthma or chronic obstructive pulmonary disease (COPD). To better understand its mechanism of action and study its dynamics, photoswitchable ligands provide a distinct advantage due to their ability to be activated with high spatiotemporal control. In this study, we developed a series of molecular tools featuring different combinations of pharmacophores, covalent warheads, and linker lengths. These compounds were characterized using highly specific assay protocols to evaluate their covalent binding capabilities, with the goal of identifying optimal covalently-bound photoswitches. Among these, the covalently-bound photoswitchable receptor agonist 6 exhibited a significant functional switch. To gain deeper insight into the binding thermodynamics and kinetics of this molecular tool, as well as the molecular determinants involved, we performed metadynamics (MetaD) simulations and analyzed their results using a Markov State Model (MSM) obtained by applying the Maximum Caliber (MaxCal) principle to the MetaD-derived free energies. These studies suggest that photoswitching of compound 6 occurs within the binding pocket of the beta 2AR. Consequently, compound 6 holds promise as a valuable tool for investigating beta 2AR activation kinetics and dynamics with high accuracy, thereby facilitating high-resolution biophysical studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | OPTICAL CONTROL; RECEPTOR; ACTIVATION; EFFICACY; INSIGHTS; AGONISTS; STATE; Computational chemistry; Covalent ligand; GPCR; Medicinal chemistry; Photopharmacology |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Sep 2026 04:46 |
| Last Modified: | 23 Sep 2026 04:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/66844 |
Actions (login required)
 |
View Item |
