Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs.

中文翻译：

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揭示舒更葡糖-罗库溴铵络合的分子动力学：环糊精药物设计的蓝图

Sugammadex（商品名 Bridion™）是一种经批准的基于环糊精 (CD) 的药物，用于逆转接受手术的成人的神经肌肉阻滞。 Sugammadex 与神经肌肉阻滞剂 (NMBA) 罗库溴铵形成包合物，可快速逆转肌肉麻痹。已经开发出研究 CD 包合物的方法，旨在准确预测其结构、能量、动力学和动力学特性以及结合常数。在这里，提出了一项计算研究，旨在从对接计算、自由分子动力学（MD）模拟和具有平均力（PMF）计算潜力的偏动力学模拟的角度来表征舒更葡糖-罗库溴铵系统。目的是提供有关该系统的详细信息，并将其用作验证方法的模型系统。该方法预测的结果与最佳结构和结合常数的定量值的实验证据一致。有趣的是，对取向的偏好不如基于静电相互作用的假设那么深刻，这表明两种取向都可能存在于溶液中。这些结果表明，该技术可以有效地分析CD包合物，并可用于促进CD新应用的开发和优化。