UNIQUE BINDING OF A NOVEL SYNTHETIC INHIBITOR TO BOVINE TRYPSIN. Yoshihiko Odagaki,+Hisao Nakai,+Kazuhiko Senokuchi, +Masanori Kawamura,+Nobuyuki Hamanaka,+Masahiro Nakamura,[[section]]Koji Tomoo[[section]] and Toshimasa Ishida[[section]] +Ono Pharmaceutical Co., Ltd. [[section]]Osaka University of Pharmaceutical Sciences
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 P212121 with cell constants a = 63.74 Å, b = 63.08 Å and c =69.38 Å, nearly identical to that of the orthorhombic crystal of guanidinobenzoyl-trypsin. The structure was solved by molecular replacement and 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. Based on 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 and its low rate of deacylation through an " inverse-substrate mechanism.
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N-[3-[4-[4-(amidinophenoxy)-carbonyl]phenyl]-2-methyl-2-propenoyl]-N-allylglycine methanesulfonate 1
References
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Tanizawa, K. et. al. (1977) J. Am. Chem. Soc. 99, 4485-4488.