Tsai A L, Strobel-Jager E, Wu K K
Department of Internal Medicine, University of Texas Health Science Center, Houston 77030.
J Comput Aided Mol Des. 1991 Apr;5(2):135-48. doi: 10.1007/BF00129752.
To elucidate the conformation of receptor-associated prostacyclin (PGI2), we first performed structure-activity correlation analysis of over 200 PGI2 analogues and derived from this analysis several crucial features pertaining to structural requirements for PGI2 activity [Ah-lim Tsai and Kenneth K. Wu, Eicosanoids, 2 (1989) 131-143]. These structural features proved to be useful guidelines for selecting 'model molecules' for further investigations by molecular mechanics. By properly selecting four analogues with either rigid or uniquely oriented alpha-side chain structure for geometric fitting, we succeeded in maximally minimizing the degree of freedom of the carboxylate terminus of PGI2. We were able to define the spatial relationship among the four critical functional groups, i.e., C1-COOH, C6a-O, C11-OH and C15-OH. More information is needed, however, to define the geometry of the omega-side chain, particularly for the moiety beyond C15. Nevertheless, results from structure-activity correlation analysis and molecular modeling provide useful information regarding the conformation of receptor-associated PGI2, which assumes an 'elongated' conformation instead of the traditional 'hairpin' structure.
为了阐明受体相关前列环素（PGI2）的构象，我们首先对200多种PGI2类似物进行了构效关系分析，并从该分析中得出了几个与PGI2活性的结构要求相关的关键特征[蔡阿林和吴健雄，类花生酸，2（1989）131 - 143]。这些结构特征被证明是通过分子力学选择“模型分子”进行进一步研究的有用指导。通过适当地选择具有刚性或独特取向的α - 侧链结构的四种类似物进行几何拟合，我们成功地最大限度地减少了PGI2羧基末端的自由度。我们能够确定四个关键官能团之间的空间关系，即C1 - COOH、C6a - O、C11 - OH和C15 - OH。然而，需要更多信息来确定ω - 侧链的几何形状，特别是C15以外的部分。尽管如此，构效关系分析和分子建模的结果提供了关于受体相关PGI2构象的有用信息，其呈现出“伸长”的构象而非传统的“发夹”结构。
