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Photopharmacology of Ion Channels through the Light of the Computational Microscope

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 tethere...

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Autores principales: Nin-Hill, Alba, Mueller, Nicolas Pierre Friedrich, Molteni, Carla, Rovira, Carme, Alfonso-Prieto, Mercedes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584574/
https://www.ncbi.nlm.nih.gov/pubmed/34769504
http://dx.doi.org/10.3390/ijms222112072
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author Nin-Hill, Alba
Mueller, Nicolas Pierre Friedrich
Molteni, Carla
Rovira, Carme
Alfonso-Prieto, Mercedes
author_facet Nin-Hill, Alba
Mueller, Nicolas Pierre Friedrich
Molteni, Carla
Rovira, Carme
Alfonso-Prieto, Mercedes
author_sort Nin-Hill, Alba
collection PubMed
description 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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spelling pubmed-85845742021-11-12 Photopharmacology of Ion Channels through the Light of the Computational Microscope Nin-Hill, Alba Mueller, Nicolas Pierre Friedrich Molteni, Carla Rovira, Carme Alfonso-Prieto, Mercedes Int J Mol Sci Review 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. MDPI 2021-11-08 /pmc/articles/PMC8584574/ /pubmed/34769504 http://dx.doi.org/10.3390/ijms222112072 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Nin-Hill, Alba
Mueller, Nicolas Pierre Friedrich
Molteni, Carla
Rovira, Carme
Alfonso-Prieto, Mercedes
Photopharmacology of Ion Channels through the Light of the Computational Microscope
title Photopharmacology of Ion Channels through the Light of the Computational Microscope
title_full Photopharmacology of Ion Channels through the Light of the Computational Microscope
title_fullStr Photopharmacology of Ion Channels through the Light of the Computational Microscope
title_full_unstemmed Photopharmacology of Ion Channels through the Light of the Computational Microscope
title_short Photopharmacology of Ion Channels through the Light of the Computational Microscope
title_sort photopharmacology of ion channels through the light of the computational microscope
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584574/
https://www.ncbi.nlm.nih.gov/pubmed/34769504
http://dx.doi.org/10.3390/ijms222112072
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