Function of the d-Alanine:d-Alanine Ligase Lid Loop: A Molecular Modeling and Bioactivity Study

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• 作者：Martina Hrast ; Bla啪 Vehar ; Samo Turk ; Janez Konc ; Stanislav Gobec ; Du拧anka Jane啪i膷
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6849-6856
• 全文大小：473K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

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.