Determination of key receptor–ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model

The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D 2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D 2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics:63. The quality of the CoMFA model was confirmed by high value of R 2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.

show abstract

“…Sukalovic et al (2013) used D 3 receptor as a template while Kołaczkowski et al (2013) compared models built on both templates.…”

Section: Homology Modelingmentioning

confidence: 99%

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Docking analysis of selected compounds (Table ) showed the following results: Compounds 11 – 18 bind to D 2 DAR in the usual manner inside the orthosteric bind site (OBS). Arylpiperazine, tail part of the ligand, binds into receptor OBS's hydrophobic pocket, formed by Phe386 6.52 , Trp390 6.48 , and Tyr420 7.43 . A short salt bridge is present between Asp114 3.32 on D 2 DAR and the protonated nitrogen atom of the compound.…”

Section: Resultsmentioning

confidence: 99%

“…Arylpiperazine, tail part of the ligand, binds into receptor OBS's hydrophobic pocket, formed by Phe386 6.52 , Trp390 6.48 , and Tyr420 7.43 [11,12]. A short salt bridge is present between Asp114 3.32 on D 2 DAR and the protonated nitrogen atom of the compound.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological, and Computational Evaluation of Substituted 1‐(2‐Methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐Methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines as Dopaminergic Ligands

Penjišević

Šukalović

Andrić

et al. 2016

Archiv der Pharmazie

View full text Add to dashboard Cite

Sixteen new 1-(2-methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines and 1-(2-methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]piperazines were synthesized to be used as probes for mapping the dopamine D2 receptor (D2 DAR) arylpiperazine binding site. All compounds were evaluated for their affinity toward D2 DAR in an in vitro competitive displacement assay. The most active one was 1-(2-methoxyphenyl)-4-{[1-(3-nitrophenethyl)piperidin-4-yl]methyl}piperazine (25) with an affinity of Ki = 54 nM. Docking analysis was conducted on all herein described compounds, whereas molecular dynamic simulation was performed on ligand 25 to establish its mode of interaction with D2 DAR. Two possible docking orientations are proposed; the one with a salt bridge between the piperidine moiety and Asp114 of D2 DAR is more stable.

show abstract

“…2,5 In this publication, the role of Phe 189, His 397 and Asn 186 in ligand binding was stressed. 2,5 In this publication, the role of Phe 189, His 397 and Asn 186 in ligand binding was stressed.…”

Section: Resultsmentioning

confidence: 99%

“…2,5 The 3D structures of the ligand were generated using the Discovery Studio program. The receptor binding site was defined to include all key amino acid residues, as described previously.…”

Section: Docking Analysismentioning

confidence: 99%

Investigation of key interactions between the second extracellular loop of dopamine D2 receptor and several hydroxy-N-{[2-(4-phenyl-piperaziny-1-yl)ethyl]phenyl}-nicotinamides

Šukalović

Šoškić²,

Ignjatović³

et al. 2014

JSCS

Self Cite

View full text Add to dashboard Cite

The dopaminergic receptor system has been the focus for the development of new pharmacotherapeutic agents targeting a number of central nervous system related disorders, such as drug addiction, schizophrenia, depression, and Parkinson's disease, to name just a few. To date, the crystal structure for the human D2 receptor is not known, despite its vital function and importance as a therapeutic target. Herein, a recent advancement in the determination of key receptor-ligand interactions for the available arylpiperazine-like ligands, using a D2 receptor model based on the crystal structure of the D3 receptor is presented. To determine key interactions responsible for high dopaminergic activity, computer-docking analysis was used together with experimental data. A total of 4 dopaminergic ligands showing moderate to high affinity were tested and the obtained results rationalized using ligand structures docked into the proposed D2 receptor model.

show abstract

Determination of key receptor–ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model

Cited by 14 publications

References 23 publications

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Synthesis, Biological, and Computational Evaluation of Substituted 1‐(2‐Methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐Methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines as Dopaminergic Ligands

Investigation of key interactions between the second extracellular loop of dopamine D2 receptor and several hydroxy-N-{[2-(4-phenyl-piperaziny-1-yl)ethyl]phenyl}-nicotinamides

Contact Info

Product

Resources

About