Exploring the Sn binding pockets in gingipains by newly developed inhibitors:: Structure-based design, chemistry, and activity
Exploring the Sn binding pockets in gingipains by newly developed inhibitors:: Structure-based design, chemistry, and activity
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DOI：
10.1021/jm0600141
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发表时间：
2006-03-09
影响因子：
7.3
通讯作者：
Mucha, A
中科院分区：
文献类型：
--
作者：
Bialas, A;Grembecka, J;Mucha, A
牙龈卟啉菌蛋白酶（Arg-gingipain，Rgps）和牙龈卟啉菌蛋白酶（Lys-gingipain，Kgp）是由牙龈卟啉单胞菌（Porphyromonas gingivalis）分泌的半胱氨酸蛋白酶，是引起牙周病的主要病原菌。牙龈蛋白酶对于细菌的毒力和存活是必不可少的，并且针对这些蛋白质的抑制剂的开发提供了治疗牙周疾病的方法。在这里，我们提出了第一个例子的gingipains抑制剂的结构为基础的设计，与使用的晶体结构的RgpB和同源模型的Kgp。氯甲基酮被选为合适的化合物，以探索这两种酶的Sn结合区域的特异性。设计、合成并测试了P1位含Arg或Lys、P2和P3位含不同取代基的三个系列的抑制剂。对于小配体，例如二肽类似物，实现了高效力（k（obs）/[I]类似于10（7）M-1 s（-1））。锡结合口袋的详细分析揭示了抑制亲和力的分子基础，并提供了深入的结构-活性关系。
Arg-gingipains (Rgps) and Lys-gingipain (Kgp) are cysteine proteinases secreted by Porphyromonas gingivalis, the major pathogen implicated in periodontal disease. Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure-based design of gingipains inhibitors, with the use of the crystal structure of RgpB and the homology model of Kgp. Chloromethyl ketones were selected as suitable compounds to explore the specificity of the Sn binding region of both enzymes. Three series of inhibitors bearing Arg or Lys at P1 and different substituents at P2 and P3 were designed, synthesized, and tested. High potency (k(obs)/[I] similar to 10(7) M-1 s(-1)) was achieved for small ligands, such as the dipeptide analogues. The detailed analysis of Sn binding pockets revealed the molecular basis of inhibitory affinity and provided insight into the structure-activity relationship.