Abstract
Autolysin E (AtlE) is a cell wall degrading enzyme that catalyzes the hydrolysis of the β-1,4-glycosidic bond between the N-acetylglucosamine and N-acetylmuramic acid units of the bacterial peptidoglycan. Using our recently determined crystal structure of AtlE from Staphylococcus aureus and a combination of pharmacophore modeling, similarity search, and molecular docking, a series of (Phenylureido)piperidinyl benzamides were identified as potential binders and surface plasmon resonance (SPR) and saturation-transfer difference (STD) NMR experiments revealed that discovered compounds bind to AtlE in a lower micromolar range. (phenylureido)piperidinyl benzamides are the first reported non-substrate-like compounds that interact with this enzyme and enable further study of the interaction of small molecules with bacterial AtlE as potential inhibitors of this target.
Keywords:
Autolysin E; SPR; STD NMR; glycoside hydrolase; virtual screening.
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Dose-Response Relationship, Drug
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Drug Discovery*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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N-Acetylmuramoyl-L-alanine Amidase / antagonists & inhibitors*
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N-Acetylmuramoyl-L-alanine Amidase / chemistry
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N-Acetylmuramoyl-L-alanine Amidase / metabolism
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology*
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / enzymology
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Piperidines
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N-Acetylmuramoyl-L-alanine Amidase
Grants and funding
The authors acknowledge the financial support from the Slovenian Research Agency [research core funding No. P1–0017, P1–0012, P1-0048 and J1-8145].