Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/115606
Title: Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
Author: Dalton, James A. R.
Lans, Isaias
Rovira, Xavier
Malhaire, Fanny
Gómez Santacana, Xavier
Pittolo, Silvia
Gorostiza Langa, Pablo Ignacio
Llebaria Soldevila, Amadeu
Goudet, Cyril
Pin, Jean-Philippe
Giraldo, Jesús
Issue Date: 1-May-2016
Publisher: Bentham Science
Abstract: Metabotropic glutamate receptors (mGluRs) are important drug targets because of their involvement in several neurological diseases. Among mGluRs, mGlu5 is a particularly high-profile target because its positive or negative allosteric modulation can potentially treat schizophrenia or anxiety and chronic pain, respectively. Here, we computationally and experimentally probe the functional binding of a novel photoswitchable mGlu5 NAM, termed alloswitch-1, which loses its NAM functionality under violet light. We show alloswitch-1 binds deep in the allosteric pocket in a similar fashion to mavoglurant, the co-crystallized NAM in the mGlu5 transmembrane domain crystal structure. Alloswitch-1, like NAM 2-Methyl-6-(phenylethynyl)pyridine (MPEP), is significantly affected by P655M mutation deep in the allosteric pocket, eradicating its functionality. In MD simulations, we show alloswitch-1 and MPEP stabilize the co-crystallized water molecule located at the bottom of the allosteric site that is seemingly characteristic of the inactive receptor state. Furthermore, both NAMs form H-bonds with S809 on helix 7, which may constitute an important stabilizing interaction for NAM-induced mGlu5 inactivation. Alloswitch-1, through isomerization of its amide group from trans to cis is able to form an additional interaction with N747 on helix 5. This may be an important interaction for amide-containing mGlu5 NAMs, helping to stabilize their binding in a potentially unusual cis-amide state. Simulated conformational switching of alloswitch-1 in silico suggests photoisomerization of its azo group from trans to cis may be possible within the allosteric pocket. However, photoexcited alloswitch-1 binds in an unstable fashion, breaking H-bonds with the protein and destabilizing the co-crystallized water molecule. This suggests photoswitching may have destabilizing effects on mGlu5 binding and functionality.
Note: Reproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417
It is part of: Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454
Related resource: http://dx.doi.org/10.2174/1570159X13666150407231417
URI: http://hdl.handle.net/2445/115606
ISSN: 1570-159X
Appears in Collections:Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

Files in This Item:
File Description SizeFormat 
L01_2016_Current Neuropharmacology_14_441_OA.pdf881.87 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.