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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective

Author(s): James A.R. Dalton, Isaias Lans, Xavier Rovira, Fanny Malhaire, Xavier Gómez-Santacana, Silvia Pittolo, Pau Gorostiza, Amadeu Llebaria, Cyril Goudet, Jean-Philippe Pin and Jesús Giraldo

Volume 14 , Issue 5 , 2016

Page: [441 - 454] Pages: 14

DOI: 10.2174/1570159X13666150407231417

Price: $65

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.

Keywords: Allosteric modulation, docking, metabotropic glutamate receptor, molecular dynamics, mutation, protein structure, transmembrane domain.

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