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Modeling key interactions between the second extracellular loop of the dopamine D2 receptor and arylpiperazine ligands

Modelovanje ključnih interakcija između druge ekstracelularne petlje dopaminskog D2 receptora i arilpiperazina kao liganada

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Authors
Šukalović, Vladimir
Šoškić, Vukić
Andrić, Deana
Roglić, Goran
Kostić Rajačić, Slađana
Article (Published version)
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Abstract
Second extracellular loop (ecl2) of the dopamine (DA) D2 receptor is an essential part of the binding pocket of dopaminergic ligands. To form a part of the ligand-binding surface, it has to fold down into the transmembrane domain of the DA receptor. The current study describes the modeling of the D2 DA receptor ecl2 and its interactions with arylpiperazine ligands. In order to model the D2 DA receptor ecl2, several arylpiperazine ligands were used to propose a pharmacophore model. D2 DA receptor ecl2 model was built using Accelrys Discovery Studio. To test the proposed model, docking analysis was performed and key amino acid residues were determined. The proposed receptor-ligand interactions were rationalized and compared with measured binding affinities. It is shown that D2 DA receptor ecl2 significantly participates in the formation of the receptor-ligand complex through aromatic, hydrophobic and polar interaction. Considering them would benefit molecular modeling of G- protein-coupl...ed receptors (GPCRs) and facilitate the design of novel active compounds.

Druga ekstracelularna petlja dopaminskog D2 receptora je esencijalni deo vezivnog mesta receptora. Da bi se definisala gornja strana vezivnog mesta, ona mora da se savije nadole, i orijentiše ka transmembranskom domenu receptora. U ovom radu opisan je proces modelovanja druge ekstracelularne petlje dopaminskog D2 receptora i njene interakcije sa arilpiperazinskim ligandima. Za modelovanje je korišćen Accelrys Discovery Studio paket programa. Predloženi model je testiran doking analizom literaturno dostupnih liganada i poređenjem dobijenih rezultata sa njihovim afinitetom vezivanja za D2 receptor. Određeni su amino-kiselinski ostaci koji stupaju u interakcije sa ligandima. Ključne interakcije su definisane i upoređene sa afinitetima liganada prema receptoru kako bi se predloženim modelom objasnile razlike u eksperimentalnim rezultatima. Naša istraživanja su pokazala da druga ekstracelularna petlja dopaminskog D2 receptora može stupati u različite interakcije sa arilpiperazinskim ligandi...ma koje između ostalih uključuju hidrofobne, aromatične interakcije ali i vodnonične veze. Ova saznanja, u kombinaciji sa predloženim modelom D2 receptora, koji uključuje ekstracelularne petlje, mogu biti od velike koristi prilikom budućeg dizajna novih dopaminergičkih liganada.

Keywords:
extracellular loop / dopamine / arylpiperazine / molecular modeling / GPRC
Source:
Journal of the Serbian Chemical Society, 2012, 77, 3, 259-277
Publisher:
  • Serbian Chemical Soc, Belgrade
Projects:
  • Structure-activity relationship of newly synthesized biological active compound (RS-172032)

DOI: 10.2298/JSC111028212S

ISSN: 0352-5139

WoS: 000302393000001

Scopus: 2-s2.0-84859047285
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URI
http://cer.ihtm.bg.ac.rs/handle/123456789/1022
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