Inagaki Hiroaki, Tsuruoka Hiroyuki, Hornsby Michael, Lesley Scott A, Spraggon Glen, Ellman Jonathan A
Department of Chemistry, University of California, Berkeley, California 94720, USA.
J Med Chem. 2007 May 31;50(11):2693-9. doi: 10.1021/jm070111+. Epub 2007 May 1.
The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 microM Ki value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to >1000-fold selectivity relative to cathepsins B, L, and K.
底物活性筛选（SAS）方法是一种基于底物的片段识别和优化方法，用于开发酶抑制剂，此前已应用于组织蛋白酶S，以获得一种新型的（2-芳基苯氧基）乙醛抑制剂2，其Ki值为0.49微摩尔（伍德，W.J.L.；帕特森，A.W.；鹤冈，H.；贾因，R.K.；埃尔曼，J.A.《美国化学会志》2005年，127卷，15521 - 15527页）。在本文中，我们公布了组织蛋白酶S与抑制剂2复合物的X射线结构，该结构揭示了一种前所未有的结合模式。基于此结构，设计了切割效率大幅提高的其他2 - 联芳氧基底物。将优化后的底物转化为相应的醛抑制剂，得到了一种低分子量（304道尔顿）且高效（9.6纳摩尔）的组织蛋白酶S抑制剂，相对于组织蛋白酶B、L和K，其选择性为100至>1000倍。
