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首页> 外文期刊>Journal of chemical information and modeling >Microswitches for the Activation of the Nociceptin Receptor Induced by Cebranopadol: Hints from Microsecond Molecular Dynamics
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Microswitches for the Activation of the Nociceptin Receptor Induced by Cebranopadol: Hints from Microsecond Molecular Dynamics

机译：用于激活蠕虫盆诱导的伤虫蛋白受体的微动开关：微秒分子动力学的提示

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摘要

Cebranopadol (CBP) is a novel analgesic acting as agonist at the nociceptin (NOP) and mu-opioid (MOP) receptors, exhibiting high potency and efficacy as an antinociceptive and antihypersensitive drug. The binding conformation and the dynamical interactions of CBP with the NOP receptor have been investigated by molecular docking, molecular dynamics (MD) in the microsecond time scale, and hybrid quantum mechanics/molecular mechanics (QM/MM). CBP binds to the NOP receptor as a bidentate ligand of the aspartate D130(3,32) by means of both its fluoroindole and dimethyl nitrogens. Starting from the known crystal structure of the inactive state of the receptor, in complex with the antagonist compound-24 (NOP-C24) the comparative analysis of 1 its MD trajectories of the NOP-C24 complex itself and the NOP_free and NOP-CBP complexes provides new insights on the already known microswitches related to receptor activation, in the frame of the extended ternary complex model. The agonist acts by destabilizing the inactive conformation of the NOP receptor, by inducing a conformational change of M134(3,36), which allows W276(6,48) to flip around its chi(2) dihedral, going in close proximity to the receptor hydrophobic core (T138(3,40) P227(5,50) F272(6,44)), which is known to be fundamental for the activation of the opioid receptors. A complete rational, picture is also provided for the role of N133(3,35) and W276(6,48) undergoing critical conformational changes related to an anticooperativity effect, i.e. the well-known role of sodium as negative modulator of agonist binding. Finally, the movement of residue Y319(7,53) belonging to the NPxxY motif is also induced by the binding of the agonist in the inactive state, opening a gate for a water channel just as upon receptor activation.
机译：Cebranopadol（CBP）是一种新的镇痛剂，作为伤害蛋白（NOP）和MU-阿片类药物（MOP）受体的激动剂，表现出高效力和功效作为抗闭合体和抗粘合剂药物。通过微秒刻度的分子对接，分子动力学（MD）和混合量子力学/分子力学（QM / mm），研究了CBP与NOP受体的结合构象和CBP的动态相互作用。 CBP通过其氟代吲哚和二甲基硝基聚合为天冬氨酸D130（3,32）的二齿配体作为双齿配体与NOP受体结合。从受体的已知晶体结构开始，与拮抗剂化合物-24（NOP-C24）复合物，NOP-C24复合物本身的1个MD轨迹的比较分析和NOP_FREE和NOP-CBP络合物在延长三元复杂模型的框架中，为已知的与受体激活相关的已知的微型开关提供了新的见解。通过诱导M134（3,36）的构象变化，使得NOP受体的无活性构象稳定，允许W276（6,48）翻转其奇异（2）二面向，靠近其奇异于（2），靠近其受体疏水芯（T138（3,40）P227（5,50）F272（6,44）），已知是对阿片受体的激活的基础。还提供了完整的理性的图片，用于N133（3,35）和W276（6,48）的作用，经历了与预期效应相关的关键构象变化，即钠作为激动剂结合的阴性调节剂的众所周知的作用。最后，残基Y319（7,53）属于NPxxy基序的运动也被激动剂在无活性状态下的结合诱导，与受体激活一样，为水通道开放浇口。

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