Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, 101 Żwirki i Wigury, 02-089 Warsaw, Poland.
College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences (MISMaP), University of Warsaw, 2C Stefana Banacha, 02-097 Warsaw, Poland.
Molecules. 2022 Mar 8;27(6):1757. doi: 10.3390/molecules27061757.
Vitamins D are a group of fat-soluble secosteroids which play a regulatory role in the functioning of most cells. Rational design of new vitamin D analogs, of increased therapeutic potency and lowered calcemic side effects, requires high-resolution initial structures and a deep understanding of interactions with the molecular targets. In this paper, using quantum crystallography, we present the first determination of the experimental quantitative charge density of an advanced intermediate of vitamin D analogues as well as a reconstruction of the theoretical electron density of final vitamin D analogues. Application of these methods allows for topological and electrostatic interaction energy analysis. We showed that the A-ring chair conformation has a significant influence on the topological properties of vitamin D compounds. Moreover, the interactions between the CD-ring and side-chain additionally stabilize the crystal structure. These results are supported by our theoretical calculations and previous biological studies.
维生素 D 是一类脂溶性甾体化合物，在大多数细胞的功能中发挥调节作用。为了合理设计具有更高治疗效力和更低钙代谢副作用的新型维生素 D 类似物，需要高分辨率的初始结构和对与分子靶标相互作用的深入了解。在本文中，我们使用量子晶体学，首次确定了维生素 D 类似物的一种高级中间体的实验定量电荷密度，以及最终维生素 D 类似物的理论电子密度的重建。这些方法的应用允许进行拓扑和静电相互作用能分析。我们表明，A 环椅构象对维生素 D 化合物的拓扑性质有显著影响。此外，CD 环和侧链之间的相互作用进一步稳定了晶体结构。这些结果得到了我们的理论计算和以前的生物学研究的支持。
