The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands

<p>G-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction of universal pharmacophore models for D2R ligands were also studied. The key amino acids, which contributed to the regular activation of the D2R, were in detail investigated by means of normal mode analysis (NMA). A derived cross-correlation matrix provided us an understanding of the degree of pair residue correlations. Although negative correlations were not observed in the case of the inactive D2R state, a high degree of correlation appeared between the residues in the active state. NMA results showed that the cytoplasmic side of the TM5 plays a significant role in promoting of residue–residue correlations in the active state of D2R. Tracing motions of the amino acids Arg219, Arg220, Val223, Asn224, Lys226, and Ser228 in the position of the TM5 are found to be critical in signal transduction. Complementing the receptor-based modeling, ligand-based modeling was also performed using known D2R ligands. The top-scored pharmacophore models were found as 5-sited (AADPR.671, AADRR.1398, AAPRR.3900, and ADHRR.2864) hypotheses from PHASE modeling from a pool consisting of more than 100 initial candidates. The constructed models using 38 D2R ligands (in the training set) were validated with 15 additional test set compounds. The resulting model correctly predicted the pIC₅₀ values of an additional test set compounds as true unknowns.</p

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^HighR and D2^LowR 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^HighR and D2^LowR targets were −12.04 and −9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2^HighR and D2^LowR with binding affinities (<i>K</i>_i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [³H]­domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2^HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2^HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2^LowR. 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^HighR and D2^LowR 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^HighR and D2^LowR targets were −12.04 and −9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2^HighR and D2^LowR with binding affinities (<i>K</i>_i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [³H]­domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2^HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2^HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2^LowR. 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