Abstract
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.
Highlights
Photopharmacology is a discipline that aims at regulating the activities of biological systems with light
The quality of the homology models may not be sufficient for an accurate prediction of photochromic ligands (PCLs) or photoswitchable tethered ligands (PTLs) binding, especially if the sequence identity of the target protein with the template is low and/or the structural changes occurring upon ligand binding are not similar to those captured in the available experimental structures
Such experimental structural information has been complemented by computational modeling, in particular, homology modeling, molecular docking and molecular dynamics (Figure 3)
Summary
Photopharmacology ( known as optopharmacology) is a discipline that aims at regulating the activities of biological systems with light. Sci. 2021, 22, 12072 covalent conjugation of tethered ligands [13] Despite this remarkable achievement, it was still unexplained why some of the PTLs, designed based on nAChR agonists, acted instead as light-modulated antagonists [11], i.e., why the addition of the azobenzene group was changing the ligand pharmacological properties. We present some of the applications published in the literature (Tables S1–S4), where computational methods have been used to rationally design and optimize photoswitchable ligands, explain their observed effect on ion channel activity and/or identify possible tethering positions for Cys mutation. We have classified such studies depending on whether the photoswitchable ligand targets voltage- or ligand-gated ion channels (VGICs and LGICs, respectively). To the best of our knowledge, most ion channel photopharmacology studies integrating computational methods have been carried out on azobenzene-based photoswitchable ligands
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