Synthesis and Characterization of Photoswitchable Covalent Ligands for the β2-Adrenoceptor

Wirth U, Neu E, Provasi D, Feustel S, Schmidt M, Hübner H, Weikert D, Filizola M, König B, Gmeiner P (2025)

Publication Type: Journal article

Publication year: 2025

Journal

DOI: 10.1002/anie.202424038

Abstract

The β2-adrenergic receptor (β2AR) 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 β2AR. Consequently, compound 6 holds promise as a valuable tool for investigating β2AR activation kinetics and dynamics with high accuracy, thereby facilitating high-resolution biophysical studies.

Authors with CRIS profile

Involved external institutions

Icahn School of Medicine at Mount Sinai United States (USA) (US) Universität Regensburg Germany (DE)

How to cite

APA:

Wirth, U., Neu, E., Provasi, D., Feustel, S., Schmidt, M., Hübner, H.,... Gmeiner, P. (2025). Synthesis and Characterization of Photoswitchable Covalent Ligands for the β2-Adrenoceptor. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202424038

MLA:

Wirth, Ulrike, et al. "Synthesis and Characterization of Photoswitchable Covalent Ligands for the β2-Adrenoceptor." Angewandte Chemie International Edition (2025).

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