Department of Life, Health and Environmental Sciences , University of L'Aquila , L'Aquila , 67100 Italy.
Istituto di Biochimica e Biochimica Clinica , Università Cattolica del Sacro Cuore , Rome , 00168 Italy.
J Chem Inf Model. 2019 Feb 25;59(2):818-831. doi: 10.1021/acs.jcim.8b00759. Epub 2019 Jan 30.
Cebranopadol (CBP) is a novel analgesic acting as agonist at the nociceptin (NOP) and μ-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 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 μs 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, which allows W276 to flip around its χ dihedral, going in close proximity to the receptor hydrophobic core (T138, P227, F272), 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 and W276 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 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.
塞来昔布（CBP）是一种新型的镇痛剂，作为孤啡肽（NOP）和μ-阿片受体（MOP）的激动剂，作为一种抗伤害性和抗过敏药物，具有高效力和疗效。通过分子对接、微秒时间尺度的分子动力学（MD）和混合量子力学/分子力学（QM/MM）研究了 CBP 与 NOP 受体的结合构象和动态相互作用。CBP 作为天冬氨酸 D130 的双齿配体与 NOP 受体结合，其氟吲哚和二甲基氮均起作用。从受体的无活性状态的已知晶体结构开始，与拮抗剂化合物-24（NOP-C24）复合物比较 1μs MD 轨迹的 NOP-C24 复合物本身以及 NOP_free 和 NOP-CBP 复合物，为已经已知的与受体激活相关的微开关提供了新的见解，在扩展的三元复合物模型的框架内。激动剂通过使 NOP 受体的无活性构象失稳，通过诱导 M134 的构象变化起作用，这允许 W276 围绕其 χ 二面角翻转，靠近受体疏水性核心（T138、P227、F272），这对于阿片受体的激活是至关重要的。还为 N133 和 W276 经历与反协同作用相关的关键构象变化提供了完整的合理图景，即众所周知的钠离子作为激动剂结合的负调节剂的作用。最后，NPxxY 基序的残基 Y319 的运动也由无活性状态下激动剂的结合诱导，在无活性状态下打开一个水通道的门，就像受体激活一样。
