Drabik P, Politowska E, Czaplewski C, Kasprzykowski F, Lankiewicz L, Ciarkowski J
Faculty of Chemistry, University of Gdańsk, Poland.
Acta Biochim Pol. 2000;47(4):1061-6.
Physiological and pathological roles of cysteine proteases make them important targets for inhibitor development. Although highly potent inhibitors of this group of enzymes are known, their major drawback is a lack of sufficient specificity. Two cysteine protease covalent inhibitors, viz. (i) Z-RL-deoxo-V-peptide-epoxysuccinyl hybrid, and (ii) Z-RLVG-methyl-, have been developed and modeled in the catalytic pocket of papain, an archetypal thiol protease. A number of configurations have been generated and relaxed for each system using the AMBER force field. The catalytic pockets S3 and S4 appear rather elusive in view of the observed inhibitors' flexibility. This suggest rather limited chances for the development of selective structure-based inhibitors of thiol proteases, designed to exploit differences in the structure of catalytic pockets of various members of this family.
半胱氨酸蛋白酶的生理和病理作用使其成为抑制剂开发的重要靶点。尽管已知这类酶有高效的抑制剂，但其主要缺点是缺乏足够的特异性。已开发出两种半胱氨酸蛋白酶共价抑制剂，即（i）Z-RL-脱氧-V-肽-环氧琥珀酰杂化物和（ii）Z-RLVG-甲基-，并在木瓜蛋白酶（一种典型的巯基蛋白酶）的催化口袋中进行了建模。使用AMBER力场为每个系统生成并松弛了许多构型。鉴于观察到的抑制剂的灵活性，催化口袋S3和S4似乎相当难以捉摸。这表明开发基于结构的选择性巯基蛋白酶抑制剂的机会相当有限，这类抑制剂旨在利用该家族不同成员催化口袋结构的差异。
