Departments of Pharmacognosy, Pharmacology, Chemistry, and Biochemistry and National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, United States.
J Nat Prod. 2013 Feb 22;76(2):178-85. doi: 10.1021/np3006088. Epub 2013 Jan 30.
Assignment of the absolute configuration of cyclic peptides frequently yields challenges, leaving one or more stereogenic centers unassigned due to small quantities of sample and the limited utility of Marfey's or other methods for assigning amino or hydroxy acids. Here, we report isolation of kahalalide Y (1) from Bryopsis pennata for the first time; in addition, the application of a combination of molecular modeling and NOE distance constraint calculations was utilized to determine the conformation of 1 and the absolute configuration of the final stereogenic center of 1. Using the Schrödinger suite, the structure of 1 was sketched in Maestro and minimized using the OPLS2005 force field in Macromodel. A conformational search was performed separately for structures having an R or S configuration at C-3 of the beta-hydroxy fatty acid subunit that completes the cyclic scaffold of 1, after which multiple minimizations for all generated conformers were carried out. The lowest energy conformers of R and S stereoisomers were then subjected to B3LYP geometry optimizations including solvent effects. The S stereoisomer was shown to be in excellent agreement with the NOE-derived distance constraints and hydrogen-bonding stability studies.
由于样品数量有限，且 Marfey 等方法在用于确定氨基酸或羟基酸的构型方面的应用有限，因此，经常会对环状肽的绝对构型进行分配，导致一个或多个手性中心未被分配。在这里，我们首次报道了从泡叶藻中分离出 kahalalide Y（1）；此外，还应用了分子建模和 NOE 距离约束计算的组合，以确定 1 的构象和 1 的最终立体中心的绝对构型。使用 Schrödinger 套件，在 Maestro 中绘制 1 的结构，并在 Macromodel 中使用 OPLS2005 力场进行最小化。对于在完成 1 的环状支架的β-羟基脂肪酸亚基的 C-3 处具有 R 或 S 构型的结构分别进行构象搜索，然后对所有生成的构象进行多次最小化。然后，将 R 和 S 立体异构体的最低能量构象进行 B3LYP 几何优化，包括溶剂效应。结果表明，S 立体异构体与 NOE 衍生的距离约束和氢键稳定性研究非常吻合。
