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:	Alba Nin-Hill, Nicolas Pierre Friedrich Mueller, Carla Molteni, Carme Rovira, Mercedes Alfonso-Prieto
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	photopharmacology photoswitchable ligands ion channels voltage-gated ion channels ligand-gated ion channels homology modeling Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/7b5bd7966e4a4393932bea7326bb5e1f
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spelling	oai:doaj.org-article:7b5bd7966e4a4393932bea7326bb5e1f2021-11-11T17:28:02ZPhotopharmacology of Ion Channels through the Light of the Computational Microscope10.3390/ijms2221120721422-00671661-6596https://doaj.org/article/7b5bd7966e4a4393932bea7326bb5e1f2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12072https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The 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.Alba Nin-HillNicolas Pierre Friedrich MuellerCarla MolteniCarme RoviraMercedes Alfonso-PrietoMDPI AGarticlephotopharmacologyphotoswitchable ligandsion channelsvoltage-gated ion channelsligand-gated ion channelshomology modelingBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12072, p 12072 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	photopharmacology photoswitchable ligands ion channels voltage-gated ion channels ligand-gated ion channels homology modeling Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	photopharmacology photoswitchable ligands ion channels voltage-gated ion channels ligand-gated ion channels homology modeling Biology (General) QH301-705.5 Chemistry QD1-999 Alba Nin-Hill Nicolas Pierre Friedrich Mueller Carla Molteni Carme Rovira Mercedes Alfonso-Prieto Photopharmacology of Ion Channels through the Light of the Computational Microscope
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.
format	article
author	Alba Nin-Hill Nicolas Pierre Friedrich Mueller Carla Molteni Carme Rovira Mercedes Alfonso-Prieto
author_facet	Alba Nin-Hill Nicolas Pierre Friedrich Mueller Carla Molteni Carme Rovira Mercedes Alfonso-Prieto
author_sort	Alba Nin-Hill
title	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_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_sort	photopharmacology of ion channels through the light of the computational microscope
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7b5bd7966e4a4393932bea7326bb5e1f
work_keys_str_mv	AT albaninhill photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT nicolaspierrefriedrichmueller photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT carlamolteni photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT carmerovira photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT mercedesalfonsoprieto photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope
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Photopharmacology of Ion Channels through the Light of the Computational Microscope

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