ArticleJournal of medicinal chemistry2026
A Systematic Benchmark Study of Free Energy Methods for Quantifying Light-Responsive Binding Affinities of Photoswitchable Antagonists of Beta-Adrenergic Receptors.
Article in Journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Multiscale Free-Energy Methods for Protonation-Coupled Light-Responsive Binding of Ionizable Photoswitchable eDHFR Inhibitors.Journal of chemical information and modeling · 2026Article
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Authors and funding
5 authors.
Funding
Abstract
Molecular photoswitches enable spatiotemporal photocontrol of protein function, but their design requires high target selectivity and large light-dependent changes in binding affinity and/or efficacy. These properties are especially difficult to optimize in membrane receptors due to membrane-protein interactions. Computational design remains challenging because few benchmarks rigorously compare free-energy methods against experiment. Here, we establish such a benchmark for photoswitchable antagonists of β-adrenergic receptors, exemplifying most successful designs in the photopharmacology of class A G protein-coupled receptors (GPCRs) to date. We evaluated widely used free-energy methods for predicting how substituents and chirality affect light-responsive binding and subtype selectivity. Thermodynamic integration shows the best agreement with experiment, followed by umbrella sampling, whereas metadynamics and end-point methods perform poorly. Our simulations reveal interactions stabilizing
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