CHARMM Force-Field Parameters for Morphine, Heroin, and Oliceridine, and Conformational Dynamics of Opioid Drugs
CHARMM Force-Field Parameters for Morphine, Heroin, and Oliceridine, and Conformational Dynamics of Opioid Drugs
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DOI：
10.1021/acs.jcim.1c00667
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发表时间：
2021-08-05
影响因子：
5.6
通讯作者：
Bondar, Ana-Nicoleta
中科院分区：
文献类型：
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作者：
Giannos, Thomas;Lesnik, Samo;Bondar, Ana-Nicoleta
阿片类药物与特殊的G蛋白偶联受体(GPCRs)结合后，可通过下游G(1)蛋白信号通路激活而产生镇痛作用，并通过激活β-arrestin信号通路而产生严重副作用。了解不同的阿片类药物如何与受体相互作用是至关重要的，因为它可以为更安全的疗法的设计提供信息和指导。我们进行了量子力学和经典力学计算，探索了四种阿片类药物：吗啡及其衍生物、海洛因和芬太尼以及与之无关的奥利克里定的势能分布。从键扭曲的势能分布和阿片类药物与水的相互作用中，我们导出了一组力场参数，这些参数可以很好地描述阿片类药物的结构性质和分子间相互作用。分子动力学模拟计算的平均作用力分布的势能表明，芬太尼和奥利克里定具有复杂的能量图景，能量损失相对较小，这表明与受体的相互作用可以选择不同的药物结合姿势。
Opioid drug binding to specialized G protein-coupled receptors (GPCRs) can lead to analgesia upon activation via downstream G(1) protein signaling and to severe side effects via activation of the beta-arrestin signaling pathway. Knowledge of how different opioid drugs interact with receptors is essential, as it can inform and guide the design of safer therapeutics. We performed quantum and classical mechanical computations to explore the potential energy landscape of four opioid drugs: morphine and its derivatives heroin and fentanyl and for the unrelated oliceridine. From potential energy profiles for bond twists and from interactions between opioids and water, we derived a set of force-field parameters that allow a good description of structural properties and intermolecular interactions of the opioids. Potential of mean force profiles computed from molecular dynamics simulations indicate that fentanyl and oliceridine have complex energy landscapes with relatively small energy penalties, suggesting that interactions with the receptor could select different binding poses of the drugs.