Identification of the Binding Modes of N-Phenylphthalimides Inhibiting Bacterial Thymidylate Synthase through X-Ray Crystallography Screening
| Autor: | Sandra Lazzari, Stefano Mangani, Maria Paola Costi, Cecilia Pozzi, Rosaria Luciani, Laura Cancian, Rosalida Leone, Stefania Ferrari |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Lactobacillus casei crystal structure Stereochemistry Molecular Sequence Data Sequence alignment Phthalimides Plasma protein binding Phenolphthalein thymidylate synthase thymdylate synthase Crystallography X-Ray Thymidylate synthase x-ray inhibitor drug discovery antibacterials enzyme inhibition phthalimides Structure-Activity Relationship Drug Discovery Enterococcus faecalis Escherichia coli Transferase Structure–activity relationship Humans Amino Acid Sequence Enzyme Inhibitors Peptide sequence chemistry.chemical_classification biology Chemistry biology.organism_classification Lacticaseibacillus casei Enzyme Biochemistry Drug Design biology.protein Molecular Medicine Sequence Alignment Protein Binding |
| Popis: | To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS enzymes and then we performed X-ray crystallographic screening of the active compounds. Compounds 6A, 8A, and 12A showed 40-fold higher affinity for bacterial TS than human TS. The X-ray crystallographic screening characterized the binding mode of six inhibitors in complexes with LcTS. Of these, 20A, 23A, and 24A showed a common unique binding mode, whereas 8A showed a different, unique binding mode. A comparative analysis of the LcTS X-ray complexes that were obtained with the pathogenic TS enabled the selection of compounds 8A and 23A as specific compounds and starting points to be exploited for the specific inhibition of pathogen enzymes. |
| Databáze: | OpenAIRE |
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