title: Structural requirements of N-substituted spiropiperidine analogues as agonists of nociceptin/orphanin FQ receptor.
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 Q(2) of 0.501, R(2) (ncv) of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R(2) (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.
authors.affiliation: Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116023, China. hedybao@dlut.edu.cn
authors.forename: Pingping
authors.initials: P
authors.lastname: Bao
authors.forename: Xiaole
authors.initials: X
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Zulin
authors.initials: Z
authors.lastname: Mu
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011957:Receptors, Opioid / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D000094942:Nociceptin Receptor
chemical_list: D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor