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首页> 外文期刊>Journal of Medicinal Chemistry >Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.
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Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.

机译：木瓜蛋白酶作为组织蛋白酶K抑制剂基于结构设计的模型的用途：两种木瓜蛋白酶抑制剂复合物的晶体结构证明与S'亚位点结合。

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摘要

Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes.
机译：木瓜蛋白酶已在药物设计工作中用作替代酶，以获取有效的和选择性的组织蛋白酶K抑制剂，组织蛋白酶K是半胱氨酸蛋白酶的木瓜蛋白酶超家族的新成员，在破骨细胞中选择性和高度表达，并与骨吸收有关。在这里，我们报告两种木瓜蛋白酶抑制剂复合物的晶体结构和新型组织蛋白酶K抑制剂的合理设计。与先前已知的木瓜蛋白酶抑制剂复合物的晶体结构不同，我们的木瓜蛋白酶结构显示出配体结合延伸至S'-亚位点深处。两种抑制剂复合物，羧苄氧基亮氨酸基-亮氨酸基-亮氨酸和羧苄氧基-L-亮氨酸基-L-亮氨酸基甲氧基甲基酮，分别以0.190和0.217的R因子精制至2.2-和2.5-A分辨率。与抑制剂的S'-亚位相互作用主要是芳族-芳族堆积和氧-芳族环边缘相互作用。对S'-位点相互作用的认识导致了一种抑制剂设计策略，该抑制剂跨越了两个位点，并产生了一种对组织蛋白酶K选择性的新型对称抑制剂。同时利用S-位点和S'-位点可以为酶的设计提供一般策略。对目标酶具有高度特异性的半胱氨酸蛋白酶抑制剂。

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