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Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines

Authorized Users Only
2004
Authors
Šukalović, Vladimir
Zlatović, Mario
Andrić, Deana
Roglić, Goran
Kostić Rajačić, Slađana
Šoškić, Vukić
Article (Published version)
,
Wiley-VCH Verlag
Metadata
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Abstract
Docking of several 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4- and 1-benzylarylpiperazines to the D 2 dopamine receptor (DAR) was examined. The binding pocket of the D 2 DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl,... CF 3 , and NO 2 ) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D 2 DAR.

Keywords:
Arylpiperazines / D2 receptor / Binding pocket
Source:
Archiv der Pharmazie, 2004, 337, 9, 502-512
Publisher:
  • Wiley-VCH Verlag

DOI: 10.1002/ardp.200400901

ISSN: 0365-6233

PubMed: 15362123

WoS: 000224140000005

Scopus: 2-s2.0-4644326189
[ Google Scholar ]
19
19
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/2822
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Šukalović, Vladimir
AU  - Zlatović, Mario
AU  - Andrić, Deana
AU  - Roglić, Goran
AU  - Kostić Rajačić, Slađana
AU  - Šoškić, Vukić
PY  - 2004
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2822
AB  - Docking of several 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4- and 1-benzylarylpiperazines to the D 2 dopamine receptor (DAR) was examined. The binding pocket of the D 2 DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF 3 , and NO 2 ) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D 2 DAR.
PB  - Wiley-VCH Verlag
T2  - Archiv der Pharmazie
T1  - Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines
VL  - 337
IS  - 9
SP  - 502
EP  - 512
DO  - 10.1002/ardp.200400901
ER  - 
@article{
author = "Šukalović, Vladimir and Zlatović, Mario and Andrić, Deana and Roglić, Goran and Kostić Rajačić, Slađana and Šoškić, Vukić",
year = "2004",
abstract = "Docking of several 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4- and 1-benzylarylpiperazines to the D 2 dopamine receptor (DAR) was examined. The binding pocket of the D 2 DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF 3 , and NO 2 ) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D 2 DAR.",
publisher = "Wiley-VCH Verlag",
journal = "Archiv der Pharmazie",
title = "Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines",
volume = "337",
number = "9",
pages = "502-512",
doi = "10.1002/ardp.200400901"
}
Šukalović, V., Zlatović, M., Andrić, D., Roglić, G., Kostić Rajačić, S.,& Šoškić, V.. (2004). Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines. in Archiv der Pharmazie
Wiley-VCH Verlag., 337(9), 502-512.
https://doi.org/10.1002/ardp.200400901
Šukalović V, Zlatović M, Andrić D, Roglić G, Kostić Rajačić S, Šoškić V. Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines. in Archiv der Pharmazie. 2004;337(9):502-512.
doi:10.1002/ardp.200400901 .
Šukalović, Vladimir, Zlatović, Mario, Andrić, Deana, Roglić, Goran, Kostić Rajačić, Slađana, Šoškić, Vukić, "Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-4-arylpiperazines" in Archiv der Pharmazie, 337, no. 9 (2004):502-512,
https://doi.org/10.1002/ardp.200400901 . .

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