Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
J Chem Inf Model. 2021 Mar 22;61(3):1251-1274. doi: 10.1021/acs.jcim.0c00890. Epub 2021 Jan 15.
Over the past two decades, the opioid epidemic in the United States and Canada has evidenced the need for a better understanding of the molecular mechanisms of medications used to fight pain. Morphine and fentanyl are widely used in opiate-mediated analgesia for the treatment of chronic pain. These compounds target the μ-opioid receptor (MOR), a class A G protein-coupled receptor (GPCR). In light of described higher efficacy of fentanyl with respect to morphine, we have performed independent μs-length unbiased molecular dynamics (MD) simulations of MOR complexes with each of these ligands, including the MOR antagonist naltrexone as a negative control. Consequently, MD simulations totaling 58 μs have been conducted to elucidate at the atomic level ligand-specific receptor activity and signal transmission in the MOR. In particular, we have identified stable binding poses of morphine and fentanyl, which interact differently with the MOR. Different ligand-receptor interaction landscapes directly induce sidechain conformational changes of orthosteric pocket residues: Asp149, Tyr150, Gln126, and Lys235. The induced conformations determine Asp149-Tyr328 sidechain-sidechain interactions and Trp295-Ala242 sidechain-backbone H-bond formations, as well as Met153 conformational changes. In addition to differences in ligand binding, different intracellular receptor conformational changes are observed as morphine preferentially activates transmembrane (TM) helices: TM3 and TM5, while fentanyl preferentially activates TM6 and TM7. As conformational changes in TM6 and TM7 are widely described as being the most crucial aspect in GPCR activation, this may contribute to the greater efficacy of fentanyl over morphine. These computationally observed functional differences between fentanyl and morphine may provide new avenues for the design of safer but not weaker opioid drugs because it is desirable to increase the safety of medicines without sacrificing their efficacy.
在过去的二十年中，美国和加拿大的阿片类药物流行证明了人们需要更好地了解用于治疗疼痛的药物的分子机制。吗啡和芬太尼广泛用于阿片类药物介导的镇痛，以治疗慢性疼痛。这些化合物靶向μ-阿片受体（MOR），一种 A 类 G 蛋白偶联受体（GPCR）。鉴于芬太尼相对于吗啡具有更高的疗效，我们已经对每种配体的 MOR 复合物进行了独立的μs 长度无偏分子动力学（MD）模拟，包括作为阴性对照的 MOR 拮抗剂纳曲酮。因此，总共进行了 58 μs 的 MD 模拟，以阐明原子水平的配体特异性受体活性和 MOR 中的信号转导。特别是，我们确定了吗啡和芬太尼的稳定结合构象，它们与 MOR 相互作用不同。不同的配体-受体相互作用景观直接诱导变构口袋残基的侧链构象变化：天冬氨酸 149、酪氨酸 150、谷氨酰胺 126 和赖氨酸 235。诱导的构象决定了天冬氨酸 149-酪氨酸 328 侧链-侧链相互作用和色氨酸 295-丙氨酸 242 侧链-骨架氢键形成，以及甲硫氨酸 153 的构象变化。除了配体结合的差异外，还观察到不同的细胞内受体构象变化，因为吗啡优先激活跨膜（TM）螺旋：TM3 和 TM5，而芬太尼优先激活 TM6 和 TM7。由于 TM6 和 TM7 中的构象变化被广泛描述为 GPCR 激活的最关键方面，这可能导致芬太尼比吗啡更有效。芬太尼和吗啡之间观察到的这些计算上的功能差异可能为设计更安全但不是更弱的阿片类药物提供新途径，因为在不牺牲疗效的情况下增加药物的安全性是可取的。
