European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg.
Nat Prod Rep. 2012 May 1;29(5):536-54. doi: 10.1039/c2np00098a. Epub 2012 Mar 29.
Covering: up to 2011. Natural products are of tremendous importance in both traditional and modern medicine. For medicinal chemistry natural products represent a challenge, as their chemical synthesis and modification are complex processes, which require many, often stereo-selective, synthetic steps. A prerequisite for the design of analogs of natural products, with more accessible synthetic routes, is the availability of their bioactive conformation. Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray crystallography are the two techniques of choice to investigate the structure of natural products. In this review, I describe the most recent advances in NMR to study the conformation of natural products either free in solution or bound to their cellular receptors. In chapter 2, I focus on the use of residual dipolar couplings (RDC). On the basis of a few examples, I discuss the benefit of complementing classical NMR parameters, such as NOEs and scalar couplings, with dipolar couplings to simultaneously determine both the conformation and the relative configuration of natural products in solution. Chapter 3 is dedicated to the study of the structure of natural products in complex with their cellular receptors and is further divided in two sections. In the first section, I describe two solution-state NMR methodologies to investigate the binding mode of low-affinity ligands to macromolecular receptors. The first approach, INPHARMA (Interligand Noes for PHArmacophore Mapping), is based on the observation of interligand NOEs between two small molecules binding competitively to a common receptor. INPHARMA reveals the relative binding mode of the two ligands, thus allowing ligand superimposition. The second approach is based on paramagnetic relaxation enhancement (PRE) of ligand resonances in the presence of a receptor containing a paramagnetic center. In the second section, I focus on solid-state NMR spectroscopy as a tool to access the bioactive conformation of natural products in complex with macromolecular receptors.
截至 2011 年。天然产物在传统和现代医学中都具有重要意义。对于药物化学来说，天然产物是一个挑战，因为它们的化学合成和修饰是复杂的过程，需要许多、往往是立体选择性的合成步骤。设计具有更易接近的合成途径的天然产物类似物的前提是获得其生物活性构象。核磁共振（NMR）光谱和 X 射线晶体学是研究天然产物结构的两种首选技术。在这篇综述中，我描述了 NMR 研究天然产物在溶液中或与细胞受体结合时构象的最新进展。在第 2 章中，我重点介绍了残余偶极耦合（RDC）的应用。基于一些例子，我讨论了用偶极耦合补充经典 NMR 参数（如 NOE 和标量耦合）来同时确定天然产物在溶液中的构象和相对构型的好处。第 3 章专门研究天然产物与其细胞受体复合物的结构，并进一步分为两个部分。在第一部分中，我描述了两种溶液态 NMR 方法来研究低亲和力配体与大分子受体的结合模式。第一种方法，INPHARMA（用于药效团映射的配体间 NOE），基于观察两个小分子与共同受体竞争结合时的配体间 NOE。INPHARMA 揭示了两个配体的相对结合模式，从而允许配体叠加。第二种方法基于含有顺磁中心的受体存在时配体共振的顺磁弛豫增强（PRE）。在第二部分中，我专注于固态 NMR 光谱作为一种获取与大分子受体结合的天然产物的生物活性构象的工具。
