Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology , Tarnaka, Hyderabad AP-500 007, India.
J Med Chem. 2013 Jul 11;56(13):5295-305. doi: 10.1021/jm400395p. Epub 2013 Jun 27.
Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.
甲硫氨酸氨肽酶（MetAPs）是一类必需的酶，使其成为癌症和微生物感染的理想药物靶点。MetAPs 从每个活细胞中新合成的肽中去除起始甲硫氨酸。MetAPs 广泛分为 I 型和 II 型。原核生物和真核生物都含有 I 型 MetAPs，而真核生物则有额外的 II 型 MetAP 酶。尽管已经报道了几种针对 I 型酶的抑制剂，但亚类特异性很少。在这里，利用结核分枝杆菌、粪肠球菌和人源 MetAPs 活性位点入口的细微差异，鉴定出了三个热点，并从商业来源中选择了吡啶并嘧啶基分子来靶向这些热点。在生化评估中，38 种化合物中的许多种对这三种酶表现出不同的作用。与人类 MetAP1b 结合的四种选定抑制剂的晶体结构和分子建模研究为结合特异性提供了依据。
