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.

中文翻译：

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两种新型拮抗剂与伤害感受素受体结合的“计算机模拟”研究。

伤害感受肽受体（NOP）的拮抗剂因其可能作为抗抑郁药的临床用途而引起人们的关注。最近，通过X射线晶体学揭示了与一些基于哌啶的拮抗剂复合的NOP的结构。在这项研究中，进行了多柔性对接（MF-docking）程序，即对接到由初步分子动力学轨迹提取的多个受体构象，以及混合量子力学/分子力学（QM / MM）模拟，以提供两种新型NOP拮抗剂的结合模式，其中一种是选择性的（BTRX-246040，以前称为LY-2940094）和一种非选择性的（AT-076），即能够灭活NOP以及经典的μ-k-和δ-阿片受体（MOP KOP和DOP）。根据我们的结果，残留物D1303的关键作用 32（上标是Ballesteros-Weinstein符号）类似于通过已知的阿片受体的X射线结构得到的启发：预测分子的结合需要稍微重新调节疏水口袋（残基Y1313,33，M1343， 36，I2195,43，Q2806,52和V2836,55）位于NOP的正构位点，可容纳配体的吡啶-吡唑（BTRX-246040）或异喹啉（AT-076）部分，进而允许质子化哌啶氮可最大化与NOP残基D1303,32的相互作用（盐桥），并将芳族头夹在Y1313,33和M1343,36之间的最佳π堆积中。MF对接程序后的QM / MM优化为结合BTRX-246040和AT-076的NOP受体提供了更可能的构象，基于不同的药效基团并表现出不同的选择性。虽然可以通过与NOP特定残基的相互作用来解释BTRX-246040对NOP的高选择性，但AT-076缺乏选择性可能与其渗透到NOP的深疏水口袋中的能力有关，同时保留了非常相似的构象由拮抗剂JDTic假定的一种进入K-阿片受体。提出的结合几何形状更适合结合口袋环境，为旨在设计选择性或多功能阿片类药物的实验研究提供了线索。AT-076缺乏选择性可能与其渗透到NOP的深疏水口袋中的能力有关，同时保留了与拮抗剂JDTic进入K阿片受体所假定的构象非常相似的构象。提出的结合几何形状更适合结合口袋环境，为旨在设计选择性或多功能阿片类药物的实验研究提供了线索。AT-076缺乏选择性可能与其渗透到NOP的深疏水口袋中的能力有关，同时保留了与拮抗剂JDTic进入K阿片受体所假定的构象非常相似的构象。提出的结合几何形状更适合结合口袋环境，为旨在设计选择性或多功能阿片类药物的实验研究提供了线索。