Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

International Journal of Molecular Sciences

Pingping Bao²  Xiaole Zhang⁴  Hong Ren¹  Yan Li²  Zulin Mu²  Shuwei Zhang²  Guohui Li³ 

[1] Department of Ophthalmology, Qi Lu Hospital, Medical School of Shandong University, Jinan 250012, China; E-Mail:;Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116023, China; E-Mails:;Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; E-Mail:;Department of Mathematical Sciences, Dalian University of Technology, Dalian, Liaoning 116023, China; E-Mail:

关键词: NOP agonist;    N-substituted spiropiperidine analogues;    3D-QSAR;    molecular docking;    molecular dynamics;   

DOI  :  10.3390/ijms12128961

来源: mdpi

【 摘 要 】

The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q² of 0.501, R²_ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R²_pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.