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 78 Umeå, Sweden.
Cryst Growth Des. 2025 Feb 12;25(5):1588-1596. doi: 10.1021/acs.cgd.4c01683. eCollection 2025 Mar 5.
The detailed understanding of the conformational pathway of fluticasone, a widely prescribed medicine for allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD), from formulation to its protein-bound state, has been limited due to a lack of access to its high-resolution structures. The three-dimensional (3D) structure of fluticasone furoate remains unpublished, and the deposited structure of fluticasone propionate could be further refined due to refinement against new data. We applied microcrystal electron diffraction (MicroED) to determine the 3D structures of and in their solid states. The preferred geometries in solution were predicted by using density functional theory (DFT) calculations. A comparative analysis of the structures of and across three states (in solid state, in solution, and protein-bound conformation) revealed the course of the 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 administration. The quantitative comparison also highlights the subtle structural differences that may lead to significant changes in the 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，由于缺乏其高分辨率结构，从制剂到其蛋白结合状态的构象途径的详细了解一直有限。糠酸氟替卡松的三维（3D）结构尚未发表，丙酸氟替卡松的已沉积结构由于根据新数据进行优化而可以进一步完善。我们应用微晶电子衍射（MicroED）来确定 和 在固态下的3D结构。通过使用密度泛函理论（DFT）计算预测了溶液中的优选几何形状。对 和 在三种状态（固态、溶液态和蛋白结合构象）下的结构进行的比较分析揭示了整个转变过程中的构象变化过程。计算了最具动态性的键的势能图，揭示了它们的旋转势垒。这项研究强调了结合使用MicroED和DFT计算来全面了解药物给药过程中的构象和能量变化。定量比较还突出了可能导致药物性质发生重大变化的细微结构差异。
