Homology modeling, docking, and molecular dynamics simulation of the receptor GALR2 and its interactions with galanin and a positive allosteric modulator

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• 作者：Wen-Qi Hui ; Qi Cheng ; Tian-Yu Liu ; Qin Ouyang
• 关键词：Homology modeling ; Docking ; Galanin receptor type 2 ; Molecular dynamic simulation ; Positive allosteric modulator
• 刊名：Journal of Molecular Modeling
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：22
• 期：4
• 全文大小：1,804 KB
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• 作者单位：Wen-Qi Hui (1)
  Qi Cheng (1)
  Tian-Yu Liu (1)
  Qin Ouyang (1)
  
  1. College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

Galanin receptor type 2 (GALR2) is a class A G-protein-coupled receptor (GPCR), and it has been reported that orthosteric ligands and positive allosteric modulators (PAMs) of GALR2 could potentially be used to treat epilepsy. So far, the X-ray structure of this receptor has not been resolved, and knowledge of the 3D structure of GALR2 may prove informative in attempts to design novel ligands and to explore the mechanism for the allosteric modulation of this receptor. In this study, homology modeling was used to obtain several GALR2 models using known templates. ProSA-web Z-scores and Ramachandran plots as well as pre-screening against a test dataset of known compounds were all utilized to select the best model of GALR2. Molecular dockings of galanin (a peptide) and a nonpeptide ligand were carried out to choose the (GALR2 model)–galanin complex that showed the closest agreement with the corresponding experimental data. Finally, a 50-ns MD simulation was performed to study the interactions between the GALR2 model and the synthetic and endogenous ligands. The results from docking and MD simulation showed that, besides the reported residues, Tyr1604.60, Ile1053.32, Ala2747.35, and Tyr163ECL2 also appear to play important roles in the binding of galanin. The potential allosteric binding pockets in the GALR2 model were then investigated via MD simulation. The results indicated that the mechanism for the allosteric modulation caused by PAMs is the binding of the PAM at pocket III, which is formed by galanin, ECL2, TM2, TM3, and ECL1; this results in the disruption of the Na+-binding site and/or the Na+ ion pathway, leading to GALR2 agonism.