Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry*
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Benzothiazoles / chemical synthesis
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Benzothiazoles / chemistry
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Enzyme Assays
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Escherichia coli Proteins / antagonists & inhibitors
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Escherichia coli Proteins / chemistry
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry
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Molecular Dynamics Simulation*
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Peptide Synthases / antagonists & inhibitors
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Peptide Synthases / chemistry*
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Protein Binding
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Protein Conformation
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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Stereoisomerism
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Structure-Activity Relationship
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Thermus / enzymology
Substances
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Bacterial Proteins
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Benzothiazoles
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Escherichia coli Proteins
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Isoxazoles
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Pyrazines
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Pyrimidines
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Peptide Synthases
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D-alanylalanine synthetase