2 research outputs found
Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking
Dopamine receptor D2 (D2R) plays
an important role in the human
central nervous system and is a focal target of antipsychotic agents.
The D2<sup>High</sup>R and D2<sup>Low</sup>R dimeric models previously
developed by our group are used to investigate the prediction of binding
affinity of the LY404,039 ligand and its binding mechanism within
the catalytic domain. The computational data obtained using molecular
dynamics simulations fit well with the experimental results. The calculated
binding affinities of LY404,039 using MM/PBSA for the D2<sup>High</sup>R and D2<sup>Low</sup>R targets were −12.04 and −9.11
kcal/mol, respectively. The experimental results suggest that LY404,039
binds to D2<sup>High</sup>R and D2<sup>Low</sup>R with binding affinities
(<i>K</i><sub>i</sub>) of 8.2 and 1640 nM, respectively.
The high binding affinity of LY404,039 in terms of binding to [<sup>3</sup>H]Âdomperidone was inhibited by the presence of a guanine nucleotide,
indicating an agonist action of the drug at D2<sup>High</sup>R. The
interaction analysis demonstrated that while Asp114 was among the
most critical amino acids for D2<sup>High</sup>R binding, residues
Ser193 and Ser197 were significantly more important within the binding
cavity of D2<sup>Low</sup>R. Molecular modeling analyses are extended
to ensemble docking as well as structure-based pharmacophore model
(E-pharmacophore) development using the bioactive conformation of
LY404,039 at the binding pocket as a template and screening of small-molecule
databases with derived pharmacophore models
Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking
Dopamine receptor D2 (D2R) plays
an important role in the human
central nervous system and is a focal target of antipsychotic agents.
The D2<sup>High</sup>R and D2<sup>Low</sup>R dimeric models previously
developed by our group are used to investigate the prediction of binding
affinity of the LY404,039 ligand and its binding mechanism within
the catalytic domain. The computational data obtained using molecular
dynamics simulations fit well with the experimental results. The calculated
binding affinities of LY404,039 using MM/PBSA for the D2<sup>High</sup>R and D2<sup>Low</sup>R targets were −12.04 and −9.11
kcal/mol, respectively. The experimental results suggest that LY404,039
binds to D2<sup>High</sup>R and D2<sup>Low</sup>R with binding affinities
(<i>K</i><sub>i</sub>) of 8.2 and 1640 nM, respectively.
The high binding affinity of LY404,039 in terms of binding to [<sup>3</sup>H]Âdomperidone was inhibited by the presence of a guanine nucleotide,
indicating an agonist action of the drug at D2<sup>High</sup>R. The
interaction analysis demonstrated that while Asp114 was among the
most critical amino acids for D2<sup>High</sup>R binding, residues
Ser193 and Ser197 were significantly more important within the binding
cavity of D2<sup>Low</sup>R. Molecular modeling analyses are extended
to ensemble docking as well as structure-based pharmacophore model
(E-pharmacophore) development using the bioactive conformation of
LY404,039 at the binding pocket as a template and screening of small-molecule
databases with derived pharmacophore models