Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784597482252009472 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8584574 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ninhillalba photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT muellernicolaspierrefriedrich photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT moltenicarla photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT roviracarme photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope AT alfonsoprietomercedes photopharmacologyofionchannelsthroughthelightofthecomputationalmicroscope |