Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 15, Pages 6849-6856Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3006965
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Funding
- European Union [LSHM-CT-2004-512138]
- Ministry of Higher Education, Science, and Technology of Slovenia [P1-0002, P1-0208, L1-4039, Z1-3666]
- Slovenian Research Agency
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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.
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