...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Shape-based virtual screening, docking, and molecular dynamics simulations to identify Mtb-ASADH inhibitors
【24h】

Shape-based virtual screening, docking, and molecular dynamics simulations to identify Mtb-ASADH inhibitors

机译：基于形状的虚拟筛选，对接和分子动力学模拟，以鉴定Mtb-ASADH抑制剂

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Aspartate beta-semialdehyde dehydrogenase (ASADH) is a key enzyme for the biosynthesis of essential amino acids and several important metabolites in microbes. Inhibition of ASADH enzyme is a promising drug target strategy against Mycobacterium tuberculosis (Mtb). In this work, in silico approach was used to identify potent inhibitors of Mtb-ASADH. Aspartyl beta-difluorophosphonate (beta-AFP), a known lead compound, was used to understand the molecular recognition interactions (using molecular docking and molecular dynamics analysis). This analysis helped in validating the computational protocol and established the participation of Arg99, Glu224, Cys130, Arg249, and His256 amino acids as the key amino acids in stabilizing ligand-enzyme interactions for effective binding, an essential feature is H-bonding interactions with the two arginyl residues at the two ends of the ligand. Best binding conformation of beta-AFP was selected as a template for shape-based virtual screening (ZINC and NCI databases) to identify compounds that competitively inhibit the Mtb-ASADH. The top rank hits were further subjected to ADME and toxicity filters. Final filter was based on molecular docking analysis. Each screened molecule carries the characteristics of the highly electronegative groups on both sides separated by an average distance of 6 angstrom. Finally, the best predicted 20 compounds exhibited minimum three H-bonding interactions with Arg99 and Arg249. These identified hits can be further used for designing the more potent inhibitors against ASADH family. MD simulations were also performed on two selected compounds (NSC4862 and ZINC02534243) for further validation. During the MD simulations, both compounds showed same H-bonding interactions and remained bound to key active residues of Mtb-ASADH.
机译：天门冬氨酸β-半醛脱氢酶（ASADH）是生物合成必需氨基酸和微生物中几种重要代谢物的关键酶。抑制ASADH酶是针对结核分枝杆菌（Mtb）的有前途的药物靶向策略。在这项工作中，采用计算机方法鉴定了Mtb-ASADH的有效抑制剂。天冬氨酰β-二氟膦酸酯（β-AFP），一种已知的先导化合物，用于理解分子识别相互作用（使用分子对接和分子动力学分析）。该分析有助于验证计算方案，并确定了Arg99，Glu224，Cys130，Arg249和His256氨基酸的参与，这些氨基酸是稳定配体-酶相互作用以实现有效结合的关键氨基酸，其基本特征是与H的键合相互作用。在配体的两个末端有两个精氨酸残基。选择了β-AFP的最佳结合构象作为基于形状的虚拟筛选（ZINC和NCI数据库）的模板，以鉴定竞争性抑制Mtb-ASADH的化合物。排名最高的歌曲将进一步接受ADME和毒性过滤器的处理。最终过滤器基于分子对接分析。每个被筛选的分子在两侧均具有平均间隔为6埃的高负电性基团的特征。最后，预测最准确的20种化合物与Arg99和Arg249的H键相互作用最少。这些确定的命中值可进一步用于设计针对ASADH家族的更有效的抑制剂。还对两种选定的化合物（NSC4862和ZINC02534243）进行了MD模拟，以进一步验证。在MD模拟过程中，两种化合物都显示出相同的H键相互作用，并且仍与Mtb-ASADH的关键活性残基结合。

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