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

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

1,†email, 2,†email, 3,4email, 1,* email, 1email, 1email, 4email and 5email
Received: 14 September 2011; in revised form: 10 November 2011 / Accepted: 21 November 2011 / Published: 6 December 2011
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: NOP agonist; N-substituted spiropiperidine analogues; 3D-QSAR; molecular docking; molecular dynamics
PDF Full-text Download PDF Full-Text [1334 KB, uploaded 19 June 2014 04:08 CEST]

Export to BibTeX |
EndNote


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.

AMA 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 . International Journal of Molecular Sciences. 2011; 12(12):8961-8981.

Chicago/Turabian Style

Bao, Pingping; Zhang, Xiaole; Ren, Hong; Li, Yan; Mu, Zulin; Zhang, Shuwei; Li, Guohui; Yang, Ling. 2011. " Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor ." Int. J. Mol. Sci. 12, no. 12: 8961-8981.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert