Tsai A L, Wu K K
Department of Internal Medicine, University of Texas Health Science Center, Houston 77030.
Eicosanoids. 1989;2(3):131-43.
Correlation analysis between the structural changes of PGI2 and the corresponding changes in platelet activity was performed to look into the following structural features: (1) the spatial relationship of critical functional groups, (2) conformational flexibility of the molecule as a result of chemical modification; (3) charge distribution around C6a; (4) hydrogen-bonding capability and mispairing and (5) the steric effects which resulted from chemical modifications. Our studies led to three important conclusions: (1) The C1 carboxylate and C11, C15 hydroxyl groups of PGI2 are essential for platelet activity. Modifications that change their relative positions reduce the activity. The ring structure and the C5 and C13 double bonds are molecular designs to maintain this unique geometry. (2) The C6a oxygen, although not vital to the binding geometry, is important for the biological potency. Decreasing the electronegativity of C6a oxygen leads to decreased potency. (3) We propose that any additional hydrogen-bond donor present between C1 and C15 could cause a hydrogen-bond mispairing and therefore a decreased activity. These findings should be useful for designing new PGI2 analogues and for determining the configuration of receptor-associated PGI2 by a molecular mechanics technique.
对前列环素（PGI2）的结构变化与血小板活性相应变化之间进行相关性分析，以研究以下结构特征：（1）关键官能团的空间关系；（2）化学修饰导致的分子构象灵活性；（3）C6a周围的电荷分布；（4）氢键形成能力及错配情况；（5）化学修饰产生的空间效应。我们的研究得出了三个重要结论：（1）PGI2的C1羧基以及C11、C15羟基对血小板活性至关重要。改变它们相对位置的修饰会降低活性。环结构以及C5和C13双键是维持这种独特几何形状的分子设计。（2）C6a氧虽然对结合几何形状并非至关重要，但对生物活性很重要。降低C6a氧的电负性会导致活性降低。（3）我们提出，C1和C15之间存在的任何额外氢键供体都可能导致氢键错配，从而导致活性降低。这些发现对于设计新的PGI2类似物以及通过分子力学技术确定与受体相关的PGI2的构型应该是有用的。
