Photopharmacology of Ion Channels through the Light of the Computational Microscope.
Photopharmacology of Ion Channels through the Light of the Computational Microscope.
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DOI：
10.3390/ijms222112072
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发表时间：
2021-11-08
影响因子：
5.6
通讯作者：
Alfonso-Prieto M
中科院分区：
文献类型：
--
作者：
Nin-Hill A;Mueller NPF;Molteni C;Rovira C;Alfonso-Prieto M
光控制和神经元活动的调查可以实现和进行与光开关配体。这样的化合物以模块化方式设计，结合靶蛋白的已知配体和光致变色基团，以及用于拴系配体的另外的亲电子基团。这样的设计策略可以通过包括结构数据来优化。除了实验结构，计算方法（如同源建模，分子对接，分子动力学和增强的采样技术）可以提供结构的见解，以指导光开关设计和理解所观察到的光调节效应。这篇综述讨论了应用这种基于结构的计算方法的光开关配体靶向电压和配体门控离子通道。结构映射可以帮助识别适合于诱变和共价连接的配体结合口袋附近的残基。在与光开关配体的复合物中的靶蛋白的建模可以揭示两种光开关异构体的不同活性和定点突变对光开关结合的影响，以及离子通道亚型选择性。这里给出的例子显示了如何将计算建模与实验数据相结合，可以大大促进光开关配体的设计和优化。结构生物学的最新进展，实验和计算，预计将进一步加强这种合理的药理学方法。
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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影响因子：
8.8
作者：
Bertaccini, Edward J.;Yoluk, Ozge;Trudell, James R.
通讯作者：
Trudell, James R.
DOI：
10.1073/pnas.1822076116
发表时间：
2019-07-30
影响因子：
11.1
作者：
Cayla, Noelie S.;Dagne, Beza A.;Bertaccini, Edward J.
通讯作者：
Bertaccini, Edward J.
DOI：
10.1073/pnas.68.8.1820
发表时间：
1971-01-01
影响因子：
11.1
作者：
BARTELS, E;WASSERMANN, NH;ERLANGER, BF
通讯作者：
ERLANGER, BF
影响因子：
2.5
作者：
Chambers, James J.;Banghart, Matthew R.;Kramer, Richard H.
通讯作者：
Kramer, Richard H.
影响因子：
25
作者：
Banghart, M;Borges, K;Kramer, RH
通讯作者：
Kramer, RH