• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>RSC Advances >A combination of docking and cheminformatics approaches for the identification of inhibitors against 4′ phosphopantetheinyl transferase of Mycobacterium tuberculosis
【24h】

A combination of docking and cheminformatics approaches for the identification of inhibitors against 4′ phosphopantetheinyl transferase of Mycobacterium tuberculosis

机译：结合对接和化学信息学方法鉴定结核分枝杆菌的4'磷酸泛肽基转移酶抑制剂

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

4′ Phosphopantetheinyl transferase (PptT) is involved in post translational modification by carrying out phosphopantetheinylation of proteins in non-ribosomal peptide synthesis and polyketide synthesis pathways of various organisms. PptT was recently shown to be crucial for the survival as well as persistence of Mycobacterium tuberculosis (M. tb) in mice models thus demonstrating it to be an attractive drug target. By employing Autodock 4.2 and Glide, we virtually screened the filtered NCI library against the active site of PptT and out of the 205 molecules tested in vitro, 13 molecules exhibited potent enzyme inhibition with IC50 ≤ 10 μg ml?1. Further evaluation of the molecules against the in vitro growth of M. tb resulted in the identification of six compounds that exhibited inhibition of both enzyme activity as well as M. tb growth. Subsequently, a cheminformatics based structure similarity approach led to the identification of 5 analogues of P-52 (IC50 – 2.25 μg ml?1 and MIC90 – 77.5 μg ml?1) with IC50 ≤ 1 μg ml?1 thereby establishing N,N-diethyl-N′-(2-methylquinolin-8-yl)propane-1,3-diamine as one of the potent inhibitory scaffolds of PptT. The inhibitors were further evaluated for their MIC90 values as well as cytotoxicity against various mammalian cell lines. PS-40 (NSC-328398), an analogue of P-52, emerged as a potent inhibitory molecule which exhibited an IC50 of 0.25 μg ml?1, MIC90 of 10 μg ml?1 and negligible cytotoxicity with a selectivity index >10 against three mammalian cell lines tested. Thus, our study identified potent inhibitory scaffolds against 4′ phosphopantetheinyl transferase of M. tb, an important drug target of M. tb.
机译：4'磷酸泛肽基转移酶（PptT）通过在各种生物的非核糖体肽合成和聚酮化合物合成途径中进行蛋白质的磷酸泛肽化来参与翻译后修饰。最近显示，PptT对小鼠模型中结核分枝杆菌（em.M. tb ）的存活和持久性至关重要，因此证明它是有吸引力的药物靶标。通过使用Autodock 4.2和Glide，我们针对PptT的活性位点虚拟筛选了过滤后的NCI库，在205种体外测试的分子中，有13种分子表现出有效的酶抑制作用，其中IC 50 ≤10μgml ？1 。进一步评估分子对 M的体外生长的作用。 tb 导致鉴定出对酶活性和 M均具有抑制作用的6种化合物。 tb 增长。随后，基于化学信息学的结构相似性方法导致鉴定出5种P-52类似物（IC 50 – 2.25μgml ？1 和MIC 90 – 77.5μgml ？1 ），IC < sub> 50 ≤1μgml ？1 ，从而建立 N ， N -二乙基- N '-（2-甲基喹啉-8-基）丙烷-1,3-二胺作为强力的PptT抑制支架之一。进一步评估了抑制剂的MIC 90 值以及对多种哺乳动物细胞系的细胞毒性。 PS-40（NSC-328398）是P-52的类似物，以有效的抑制性分子出现，其IC 50 的IC值为0.25μgml ？1 ，MIC 90 的10μgml ？1 可以忽略不计对三种测试的哺乳动物细胞系的选择性大于10的细胞毒性。因此，我们的研究确定了针对 M的4'磷酸泛肽基转移酶的有效抑制支架。 tb ，它是 M的重要药物靶标。 tb 。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号