Photocontrol of Endogenous Glycine Receptors In Vivo

Gomila, Alexandre M. J.; Rustler, Karin; Maleeva, Galyna; Nin‐Hill, Alba; Wutz, Daniel; Bautista-Barrufet, Antoni; Rovira, Xavier; Bosch, María; Mukhametova, Elvira; Petukhova, Elena; Ponomareva, Daria; Mukhamedyarov, Marat A.; Peiretti, Franck; Alfonso‐Prieto, Mercedes; Rovira, Carme; König, Burkhard; Bregestovski, Pìotr; Gorostiza, Pau

doi:10.1016/j.chembiol.2020.08.005

Cited by 19 publications

(18 citation statements)

References 81 publications

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“…Nonetheless, GlyRs are attracting growing attention as possible targets for painkillers [ 112 , 113 ]. Two PCLs based on azobenzene and a benzodiazepine core have been developed so far [ 110 , 114 ]. The aforementioned azo-NZ1 ( 16 in Figure S3 ), as well as Glyght ( 17 ), exhibited light-modulated responses in an in vivo behavioral zebrafish assay.…”

Section: Computational Modeling Of Photoswitchable Ligands Targeting Ligand-gated Ion Channelsmentioning

confidence: 99%

“…As mentioned above, the selective inhibitory effect of Glyght ( 17 ) on GlyRs when in cis form [ 114 ] was completely unexpected. The PCL was designed based on a nitrazepam/diazepam core and GlyRs do not contain a benzodiazepine binding site.…”

Section: Computational Modeling Of Photoswitchable Ligands Targeting Ligand-gated Ion Channelsmentioning

confidence: 99%

“…Each contour line corresponds to a number density of 0.0006 particles/Å 3 . Among the several high-density regions, the interface between ECD and TMD appears to be the most likely binding region for cis -Glyght [ 114 ], as it shows the largest differences compared to the trans -Glyght blind docking (data not shown). The box size for the subsequent targeted rigid docking is indicated as a blue box.…”

Section: Figurementioning

confidence: 99%

“…Hydrophobic contacts between cis -Glyght and the receptor residues are represented as a yellow surface, while the atoms involved in receptor–ligand hydrogen bonds are represented with larger spheres and a dashed line between them. Adapted from reference [ 114 ] with permission from Cell Chemical Biology, published by Elsevier (2020).…”

Section: Figurementioning

confidence: 99%

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Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.

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Section: Computational Modeling Of Photoswitchable Ligands Targeting Ligand-gated Ion Channelsmentioning

confidence: 99%

Section: Computational Modeling Of Photoswitchable Ligands Targeting Ligand-gated Ion Channelsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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“…PCLs and PTLs contain a photoswitch whose structure can be changed reversibly upon irradiation, along with the alternation of binding circumstances. The advantage of not requiring genetic modification makes PCL a popular and convenient strategy with broad applications in many biologically-important targets, such as ionotropic or metabotropic glutamate receptors (iGlu or mGlu) (Reiner et al, 2015;Goudet et al, 2018;Pittolo et al, 2014), NMDA receptors (Berlin et al, 2016), GABA receptors (Yue et al, 2012;Lutz et al, 2018;Stein et al, 2012), protein kinase C (Frank et al, 2016), epithelial sodium channel (Schönberger et al, 2014), L-type Ca 2+ channels (Fehrentz et al, 2018), vanilloid receptor (Frank et al, 2015), microtubule (Borowiak et al, 2015), transient receptor (TRP) channels (Leinders-Zufall et al, 2018;Lichtenegger et al, 2018), glycine receptors (Gomila et al, 2020), cannabinoid receptor (Westphal et al, 2017) and potassium channel (Barber et al, 2016;Banghart et al, 2009) as well as nAChRs (Tochitsky et al, 2012;Damijonaitis et al, 2015;Deal et al, 1969;Kagabu et al, 2010). Photopharmacology studies of nAChRs advance our understanding of their roles in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

Optical Control of Invertebrate nAChR and Behaviors with Dithienylethene-Imidacloprid

Zhang¹,

Xu²,

Xu³

et al. 2021

Preprint

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Photopharmacology has changed established methods of studying receptor functions, allowing for increasing spatiotemporal resolution. However, no photopharmacological tools are available for the invertebrate nicotinic acetylcholine receptor (nAChR). Here, we report a photochromic ligand, dithienylethene-imidacloprid (DitIMI), targeting invertebrate nAChR. We demonstrated that DitIMI has low spontaneous in vivo and in vitro activity but can be photoisomerized to a highly active closed-form. This photoisomerization can further be translated to photomodulation of neuron membrane potential and behavioral responses of living mosquito larvae and American cockroaches. Furthermore, we discovered that DitIMI is a specific reporter for fluorescence polarization based high-throughput screening of nAChR ligands.

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Rational Design in Photopharmacology with Molecular Photoswitches

et al. 2023

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Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.

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Photocontrol of Endogenous Glycine Receptors In Vivo

Cited by 19 publications

References 81 publications

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Optical Control of Invertebrate nAChR and Behaviors with Dithienylethene-Imidacloprid

Rational Design in Photopharmacology with Molecular Photoswitches

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