TY - JOUR
T1 - mGluR5
T2 - Exploration of Orthosteric and Allosteric Ligand Binding Pockets and Their Applications to Drug Discovery
AU - Mølck, Christina
AU - Harpsøe, Kasper
AU - Gloriam, David E
AU - Mathiesen, Jesper M
AU - Nielsen, Søren M
AU - Bräuner-Osborne, Hans
PY - 2014/9/24
Y1 - 2014/9/24
N2 - Since its discovery in 1992, mGluR5 has attracted significant attention and been linked to several neurological and psychiatric diseases. Ligand development was initially focused on the orthosteric binding pocket, but lack of subtype selective ligands changed the focus to the transmembrane allosteric binding pocket. This strategy has resulted in several drug candidates in clinical testing. In the present article we explore the orthosteric and allosteric binding pockets in terms of structure and ligand recognition across the mGluR subtypes and groups, and discuss the clinical potential of ligands targeting these pockets. We have performed binding mode analyses of non- and group-selective orthosteric ligands based on molecular docking in mGluR crystal structures and models. For the analysis of the allosteric binding pocket we have combined data from all mGluR5-mutagenesis studies, collectively reporting five negative allosteric modulators and 47 unique mutations, and compared it to the closest related homolog, mGluR1.
AB - Since its discovery in 1992, mGluR5 has attracted significant attention and been linked to several neurological and psychiatric diseases. Ligand development was initially focused on the orthosteric binding pocket, but lack of subtype selective ligands changed the focus to the transmembrane allosteric binding pocket. This strategy has resulted in several drug candidates in clinical testing. In the present article we explore the orthosteric and allosteric binding pockets in terms of structure and ligand recognition across the mGluR subtypes and groups, and discuss the clinical potential of ligands targeting these pockets. We have performed binding mode analyses of non- and group-selective orthosteric ligands based on molecular docking in mGluR crystal structures and models. For the analysis of the allosteric binding pocket we have combined data from all mGluR5-mutagenesis studies, collectively reporting five negative allosteric modulators and 47 unique mutations, and compared it to the closest related homolog, mGluR1.
U2 - 10.1007/s11064-014-1248-8
DO - 10.1007/s11064-014-1248-8
M3 - Journal article
C2 - 24493625
SN - 0364-3190
VL - 39
SP - 1862
EP - 1875
JO - Neurochemical Research
JF - Neurochemical Research
IS - 10
ER -