Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
J Med Chem. 2012 Aug 9;55(15):6849-56. doi: 10.1021/jm3006965. Epub 2012 Jul 26.
D-Alanine:D-alanine ligase (Ddl) is an essential ATP-dependent bacterial enzyme involved in peptidoglycan biosynthesis. Discovery of Ddl inhibitors not competitive with ATP has proven to be difficult because the Ddl bimolecular d-alanine binding pocket is very restricted, as is accessibility to the active site for larger molecules in the catalytically active closed conformation of Ddl. A molecular dynamics study of the opening and closing of the Ddl lid loop informs future structure-based design efforts that allow for the flexibility of Ddl. A virtual screen on generated enzyme conformations yielded some hit inhibitors whose bioactivity was determined.
D-丙氨酸：D-丙氨酸连接酶（Ddl）是一种参与肽聚糖生物合成的必需的 ATP 依赖性细菌酶。已证明，发现不与 ATP 竞争的 Ddl 抑制剂非常困难，因为 Ddl 双分子 D-丙氨酸结合口袋非常受限，而且对于较大分子而言，在 Ddl 的催化活性闭合物构象中，进入活性位点的通道也非常受限。对 Ddl 盖环的打开和关闭的分子动力学研究为未来基于结构的设计工作提供了信息，这些设计工作允许 Ddl 具有灵活性。对生成的酶构象进行虚拟筛选得到了一些具有生物活性的命中抑制剂。
