 |
PDBsum entry 6ffh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Membrane protein
|
PDB id
|
|
|
|
6ffh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure-Based optimization strategies for g protein-Coupled receptor (gpcr) allosteric modulators: a case study from analyses of new metabotropic glutamate receptor 5 (mglu5) X-Ray structures.
|
|
|
Authors
|
|
J.A.Christopher,
Z.Orgován,
M.Congreve,
A.S.Doré,
J.C.Errey,
F.H.Marshall,
J.S.Mason,
K.Okrasa,
P.Rucktooa,
M.J.Serrano-Vega,
G.G.Ferenczy,
G.M.Keserű.
|
|
|
Ref.
|
|
J Med Chem, 2019,
62,
207-222.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Two interesting new X-ray structures of negative allosteric modulator (NAM)
ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are
reported. The new structures show how the binding of the ligands induces
different receptor water channel conformations to previously published
structures. The structure of fenobam, where a urea replaces the acetylenic
linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is
rotated by 180° compared to a previously proposed docking model. The need for
multiple ligand structures for accurate GPCR structure-based drug design is
demonstrated by the different growing vectors identified for the head groups of
M-MPEP and mavoglurant and by the unexpected water-mediated receptor
interactions of a new chemotype represented by fenobam. The implications of the
new structures for ligand design are discussed, with extensive analysis of the
energetics of the water networks of both pseudoapo and bound structures
providing a new design strategy for allosteric modulators.
|
|
|
|
|
|
|
