Odagaki Y, Nakai H, Senokuchi K, Kawamura M, Hamanaka N, Nakamura M, Tomoo K, Ishida T
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Biochemistry. 1995 Oct 3;34(39):12849-53. doi: 10.1021/bi00039a046.
Trypsin and N-[3-[4-[4-(amidinophenoxy)carbonyl]phenyl]-2-methyl-2-propenoyl]- N-allylglycine methanesulfonate (1), a newly designed and orally active synthetic trypsin inhibitor, were cocrystallized. The space group of the crystal is P2(1)2(1)2(1) with cell constants a = 63.74 A, b = 63.08 A, and c = 69.38 A, which is nearly identical to that of the orthorhombic crystal of guanidinobenzoyltrypsin. The structure was refined to a crystallographic residual R = 0.176. The refined model of the 1-trypsin complex provides the structural basis for the reaction mechanism of 1. On the basis of the present X-ray results, it is proposed that the potent inhibitory activity of 1 is mainly due to the formation of an acylated trypsin through an "inverse substrate mechanism" and its low rate of deacylation.
胰蛋白酶与N-[3-[4-[4-(脒基苯氧基)羰基]苯基]-2-甲基-2-丙烯酰基]-N-烯丙基甘氨酸甲磺酸盐(1)（一种新设计的具有口服活性的合成胰蛋白酶抑制剂）进行了共结晶。该晶体的空间群为P2(1)2(1)2(1)，晶胞参数a = 63.74 Å，b = 63.08 Å，c = 69.38 Å，这与胍基苯甲酰胰蛋白酶的正交晶体几乎相同。结构精修后的晶体学残余因子R = 0.176。1-胰蛋白酶复合物的精修模型为1的反应机制提供了结构基础。基于目前的X射线结果，有人提出1的强效抑制活性主要是由于通过“反向底物机制”形成了酰化胰蛋白酶及其低脱酰化速率。
