Journal of Computer-Aided Molecular Design

, Volume 32, Issue 2, pp 385–400 | Cite as

“In silico” study of the binding of two novel antagonists to the nociceptin receptor

  • Stefano Della Longa
  • Alessandro Arcovito


Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i.e. able to inactivate NOP as well as the classical µ- k- and δ-opioid receptors (MOP KOP and DOP). According to our results, the pivotal role of residue D1303,32 (upper indexes are Ballesteros–Weinstein notations) is analogous to that enlighten by the already known X-ray structures of opioid receptors: binding of the molecules are predicted to require a slight readjustment of the hydrophobic pocket (residues Y1313,33, M1343,36, I2195,43, Q2806,52 and V2836,55) in the orthosteric site of NOP, accommodating either the pyridine–pyrazole (BTRX-246040) or the isoquinoline (AT-076) moiety of the ligand, in turn allowing the protonated piperidine nitrogen to maximize interaction (salt-bridge) with residue D1303,32 of the NOP, and the aromatic head to be sandwiched in optimal π-stacking between Y1313,33 and M1343,36. The QM/MM optimization after the MF-docking procedure has provided the more likely conformations for the binding to the NOP receptor of BTRX-246040 and AT-076, based on different pharmacophores and exhibiting different selectivity profiles. While the high selectivity for NOP of BTRX-246040 can be explained by interactions with NOP specific residues, the lack of selectivity of AT-076 could be associated to its ability to penetrate into the deep hydrophobic pocket of NOP, while retaining a conformation very similar to the one assumed by the antagonist JDTic into the K-opioid receptor. The proposed binding geometries fit better the binding pocket environment providing clues for experimental studies aimed to design selective or multifunctional opioid drugs.


BTRX-246040 LY2940094 AT-076 Molecular dynamics Docking QM/MM GPCR Opioid receptor Antidepressant drugs NOPR antagonists OPRX N/OFQ 



This work was supported by Italian Ministry of University and Research (LINEA D1 Università Cattolica del Sacro Cuore) and by the CINECA supercomputing centers through the grants isC39 and isC48 (n. HP10CIU3D6 and HP10CXDJYH).

Author contributions

The manuscript was written through contributions of all the authors. All the authors have approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interest.

Supplementary material

10822_2017_95_MOESM1_ESM.pdf (2.5 mb)
Supplementary material 1 (PDF 2567 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Life, Health and Environmental SciencesUniversity of L’AquilaL’AquilaItaly
  2. 2.Institute of Biochemistry and Clinical BiochemistryCatholic University of Sacred HeartRomeItaly

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