Stereospecific recognition of chiral molecules plays a crucial role in biological systems. The μ-opioid receptor (MOR) exhibits binding affinity towards (-)-morphine, a well-established gold standard in pain management, while it shows minimal binding affinity for the (+)-morphine enantiomer, resulting in a lack of analgesic activity. Understanding how MOR stereo-selectively recognizes morphine enantiomers has remained a puzzle in neuroscience and pharmacology for over half a century due to the lack of direct observation techniques. To unravel this mystery, we constructed the binding and unbinding processes of morphine enantiomers with MOR via molecular dynamics simulations to investigate the thermodynamics and kinetics governing MOR’s stereoselective recognition of morphine enantiomers. Our findings reveal that the binding of (-)-morphine stabilizes MOR in its activated state, exhibiting a deep energy well and a prolonged residence time. In contrast, (+)-morphine fails to sustain the activation state of MOR. Furthermore, the results suggest that specific residues, namely D1142.50 and D1473.32, are deprotonated in the active state of MOR bound to (-)-morphine. This work highlights that the selectivity in molecular recognition goes beyond binding affinities, extending into the realm of residence time.
手性分子的立体特异性识别在生物系统中起着至关重要的作用。μ-阿片受体（MOR）对(-)-吗啡具有结合亲和力，(-)-吗啡是公认的镇痛黄金标准，而它对(+)-吗啡对映体的结合亲和力极低，因此缺乏镇痛活性。由于缺乏直接观察技术，半个多世纪以来，MOR 如何立体选择性地识别吗啡对映体一直是神经科学和药理学领域的一个难题。为了揭开这个谜团，我们通过分子动力学模拟构建了吗啡对映体与 MOR 的结合和解除结合过程，研究了 MOR 立体选择性识别吗啡对映体的热力学和动力学。我们的研究结果表明，(-)-吗啡的结合使 MOR 稳定在活化状态，表现出较深的能量井和较长的停留时间。相反，(+)-吗啡则无法维持 MOR 的活化状态。此外，研究结果表明，特定残基（即 D1142.50 和 D1473.32）在 MOR 与 (-)-morphine 结合的活性状态下被去质子化。这项工作突出表明，分子识别的选择性超出了结合亲和力的范围，延伸到了停留时间的领域。
{"title":"Stereoselective recognition of morphine enantiomers by μ-opioid receptor","authors":"Yibo Wang, A. Van Ngo, Xiaohui Wang","doi":"10.1093/nsr/nwae029","DOIUrl":"https://doi.org/10.1093/nsr/nwae029","url":null,"abstract":"\u0000 Stereospecific recognition of chiral molecules plays a crucial role in biological systems. The μ-opioid receptor (MOR) exhibits binding affinity towards (-)-morphine, a well-established gold standard in pain management, while it shows minimal binding affinity for the (+)-morphine enantiomer, resulting in a lack of analgesic activity. Understanding how MOR stereo-selectively recognizes morphine enantiomers has remained a puzzle in neuroscience and pharmacology for over half a century due to the lack of direct observation techniques. To unravel this mystery, we constructed the binding and unbinding processes of morphine enantiomers with MOR via molecular dynamics simulations to investigate the thermodynamics and kinetics governing MOR’s stereoselective recognition of morphine enantiomers. Our findings reveal that the binding of (-)-morphine stabilizes MOR in its activated state, exhibiting a deep energy well and a prolonged residence time. In contrast, (+)-morphine fails to sustain the activation state of MOR. Furthermore, the results suggest that specific residues, namely D1142.50 and D1473.32, are deprotonated in the active state of MOR bound to (-)-morphine. This work highlights that the selectivity in molecular recognition goes beyond binding affinities, extending into the realm of residence time.","PeriodicalId":507754,"journal":{"name":"National Science Review","volume":"39 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139523277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ten years of NSR—Progress and perspectives","authors":"Chun-li Bai, M. Poo","doi":"10.1093/nsr/nwae002","DOIUrl":"https://doi.org/10.1093/nsr/nwae002","url":null,"abstract":"","PeriodicalId":507754,"journal":{"name":"National Science Review","volume":"37 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139534048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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