3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor.
The nociceptin/orphanin FQ receptor (NOP) has been implicated in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have a great potential to be developed into anxiolytics. However, the crystal structure of NOP is still not available. In the present work, both structure-based and ligand-based modeling methods have been used to achieve a comprehensive understanding on 67N-substituted spiropiperidine analogues as NOP agonists. The comparative molecular-field analysis method was performed to formulate a reasonable 3D-QSAR model (cross-validated coefficient q(2)=0.819 and conventional r(2)=0.950), whose robustness and predictability were further verified by leave-eight-out, Y-randomization, and external test-set validations. The excellent performance of CoMFA to the affinity differences among these compounds was attributed to the contributions of electrostatic/hydrogen-bonding and steric/hydrophobic interactions, which was supported by the Surflex-Dock and CDOCKER molecular-docking simulations based on the 3D model of NOP built by the homology modeling method. The CoMFA contour maps and the molecular docking simulations were integrated to propose a binding mode for the spiropiperidine analogues at the binding site of NOP.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, PR China.
Ming
M
Liu
Lin
L
He
Xiaopeng
X
Hu
Peiqing
P
Liu
Hai-Bin
HB
Luo
D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D055672:Static Electricity; D040681:Structural Homology, Protein; D000094942:Nociceptin Receptor
D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor