Derivatives of Salicylic Acid as Inhibitors of YopH in Yersinia pestis
Derivatives of Salicylic Acid as Inhibitors of YopH in Yersinia pestis
复制标题
DOI：
10.1111/j.1747-0285.2010.00996.x
复制
发表时间：
2010-08-01
影响因子：
3
通讯作者：
Wong, Chung F.
中科院分区：
文献类型：
--
作者：
Huang, Zunnan;He, Yantao;Wong, Chung F.
鼠疫耶尔森氏菌引起的疾病从胃肠道综合征到腺鼠疫，可能被滥用为生物武器。由于其蛋白酪氨酸磷酸酶YopH已被证明是一个潜在的药物靶点，我们已经开发了两个系列的40个水杨酸衍生物，并发现16个具有微摩尔抑制活性。我们设计了这些配体，使其具有通过柔性烃连接体连接的两个化学部分，以靶向蛋白质活性位点中的两个口袋，以实现结合亲和力和选择性。一个部分具有水杨酸核心，旨在靶向磷酸酪氨酸结合口袋。另一部分含有不同的化学片段，旨在靶向附近的次级口袋。这两个系列的化合物的不同之处在于具有不同长度的烃连接基。在实验共晶结构可用之前，我们已经进行了分子对接来预测这些化合物如何与蛋白质结合，并生成用于进行结合亲和力计算的结构模型，以帮助这些系列化合物的未来优化。
Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site of the protein to achieve binding affinity and selectivity. One moiety possessed the salicylic acid core intending to target the phosphotyrosine-binding pocket. The other moiety contained different chemical fragments meant to target a nearby secondary pocket. The two series of compounds differed by having hydrocarbon linkers with different lengths. Before experimental co-crystal structures are available, we have performed molecular docking to predict how these compounds might bind to the protein and to generate structural models for performing binding affinity calculation to aid future optimization of these series of compounds.