Exploring Molecular Mechanisms of Ligand Recognition by Opioid Receptors with Metadynamics
Exploring Molecular Mechanisms of Ligand Recognition by Opioid Receptors with Metadynamics
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DOI：
10.1021/bi901494n
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发表时间：
2009-10-27
期刊：
影响因子：
2.9
通讯作者：
Filizola, Marta
中科院分区：
文献类型：
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作者：
Provasi, Davide;Bortolato, Andrea;Filizola, Marta
阿片受体是G蛋白偶联受体（GPCR），在开发用于治疗严重疼痛的强效镇痛药物中具有极其重要的意义。在分子水平上对这些受体的配体结合途径进行准确的评估，可能在设计具有更理想特性和减少副作用的新分子中发挥关键作用。最近的高分辨率X射线晶体结构的非视紫红质GPCR的扩散激素和神经递质的表征提供了一个前所未有的机会，建立改进的阿片受体的同源模型，并更详细地研究其配体识别的分子机制。在这项研究中，可能的途径进入非选择性拮抗剂纳洛酮（NLX）从水环境中的δ阿片受体（DOR）的分子模型的基础上的β 2-肾上腺素能受体晶体结构的生物碱结合口袋进行了探索，使用微秒尺度的良好回火代谢模拟。使用解释NLX和受体胞外环2相对于DOR结合口袋的位置的距离作为集合变量，我们能够区分配体访问的不同状态（即，对接的、未对接的和亚稳态结合的中间体），并在校正取样方法的可能缺点后预测接近实验值的结合自由能。本文所采用的策略有希望将其应用于阿片受体以及其他GPCR的不同配体的对接。
Opioid receptors are G protein-coupled receptors (GPCRs) of utmost significance in the development of potent analgesic drugs for the treatment of severe pain. An accurate evaluation at the molecular level of the ligand binding pathways into these receptors may play a key role in the design of new molecules with more desirable properties and reduced side effects. The recent characterization of high-resolution X-ray crystal structures of non-rhodopsin GPCRs for diffusible hormones and neurotransmitters presents an unprecedented opportunity to build improved homology models of opioid receptors, and to study in more detail their molecular mechanisms of ligand recognition. In this study, possible pathways for entry of the nonselective antagonist naloxone (NLX) from the water environment into the well-accepted alkaloid binding pocket of a delta opiold receptor (DOR) molecular model based on the beta 2-adrenergic receptor crystal structure are explored using microsecond-scale well-tempered metadynamics simulations. Using as collective variables distances that account for the position of NLX and of the receptor extracellular loop 2 in relation to the DOR binding pocket, we were able to distinguish between the different states visited by the ligand (i.e., docked, undocked, and metastable bound intermediates) and to predict a free energy of binding close to experimental values after correcting for possible drawbacks of the sampling approach. The strategy employed herein holds promise for its application to the docking of diverse ligands to the opioid receptors as well as to other GPCRs.