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Int. J. Mol. Sci. 2011, 12(12), 8961-8981; doi:10.3390/ijms12128961

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

1
Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116023, China
2
Department of Mathematical Sciences, Dalian University of Technology, Dalian, Liaoning 116023, China
3
Department of Ophthalmology, Qi Lu Hospital, Medical School of Shandong University, Jinan 250012, China
4
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
5
Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian, Liaoning 116023, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 14 September 2011 / Revised: 10 November 2011 / Accepted: 21 November 2011 / Published: 6 December 2011
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

Abstract

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, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred 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. View Full-Text
Keywords: NOP agonist; N-substituted spiropiperidine analogues; 3D-QSAR; molecular docking; molecular dynamics NOP agonist; N-substituted spiropiperidine analogues; 3D-QSAR; molecular docking; molecular dynamics
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Bao, P.; Zhang, X.; Ren, H.; Li, Y.; Mu, Z.; Zhang, S.; Li, G.; Yang, L. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor . Int. J. Mol. Sci. 2011, 12, 8961-8981.

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