Lin Jieye, Unge Johan, Gonen Tamir
Department of Biological Chemistry, University of California, Los Angeles, 615 Charles E. Young Drive South, Los Angeles, California 90095, United States.
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
bioRxiv. 2024 Sep 19:2024.09.18.613782. doi: 10.1101/2024.09.18.613782.
The detailed understanding of fluticasone, a widely prescribed medicine for allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD), has not been complete due to challenges in structural elucidation. The three-dimensional (3D) structure of fluticasone furoate remained undetermined for decades, while the existing structures of fluticasone propionate required refinement against improved data. In this study, we applied microcrystal electron diffraction (MicroED) to determine the 3D structures of and in their drug formulation state. Density functional theory (DFT) calculations were utilized to model solvent effects to determine the preferred geometries in solution. A comparative analysis of structures of and across three states (drug formulation state, in solution, and biologically active state) revealed major conformational changes during the entire transition. Potential energy plots were calculated for the most dynamic bonds, uncovering their rotational barriers. This study underscores the combined use of MicroED and DFT calculations to provide a comprehensive understanding of conformational and energy changes during drug functioning in humans. The quantitative comparison highlights the subtle structural differences that can lead to significant functional changes in pharmaceutical properties.
氟替卡松是一种广泛用于治疗过敏性鼻炎、哮喘和慢性阻塞性肺疾病（COPD）的药物，由于结构解析方面的挑战，对其详细了解尚未完成。糠酸氟替卡松的三维（3D）结构几十年来一直未确定，而丙酸氟替卡松的现有结构需要根据改进的数据进行优化。在本研究中，我们应用微晶电子衍射（MicroED）来确定 和 在其药物制剂状态下的3D结构。利用密度泛函理论（DFT）计算来模拟溶剂效应，以确定溶液中的优选几何结构。对 和 在三种状态（药物制剂状态、溶液状态和生物活性状态）下的结构进行的比较分析揭示了整个转变过程中的主要构象变化。计算了最具动态性的键的势能图，揭示了它们的旋转障碍。本研究强调了MicroED和DFT计算的联合使用，以全面了解药物在人体内发挥作用过程中的构象和能量变化。定量比较突出了可能导致药物性质发生显著功能变化的细微结构差异。
