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.
Highlights
nociceptin/orphanin FQ (NOP), the nociceptin/orphanin peptide, is a 17-amino acid neuropeptide which was discovered in1995 [1,2]
A number of statistical parameters, i.e., the Q2, non-cross-validated correlation coefficient (R2ncv), standard error of estimate (SEE), and F-statistic values, are analyzed to evaluate the quality of the models. In both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) analyses, ligand-based alignment modeling leads to models with larger R2cv, R2ncv, R2pred values than the corresponding models obtained by the receptor-based alignment modeling
The results show that all molecules in the series were well placed in the active site demonstrating the rationality and reliability of the docking model
Summary
NOP, the nociceptin/orphanin peptide, is a 17-amino acid neuropeptide which was discovered in1995 [1,2]. As an endogenous ligand, it binds only to its own receptor, i.e., the NOP receptor ( known as ORL1, OP4 or LC132) which was cloned in 1994 [5] and named after this ligand. NOP receptor belongs to the transmembrane G-protein coupled receptor family, and is widely distributed in the central nervous system with the highest density in the forebrain, brainstem, dorsal and ventral horns of the spinal cord. It is present in the peripheral nervous system as well as in some non-neural tissues (epidermis, immunocytes, and vascular endothelium) [6,7,8]. Due to the therapeutic potential of the NOP receptor, it has received considerable attention in research since it was cloned
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