Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure-Activity Relationship Studies
| Autor: | Robert J. Woods, Heather Strachan, Sameer Kawatkar, Shaji K. George, Bing Li, Aloysius Siriwardena, Geert-Jan Boons, Kelley W. Moremen |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Molecular model Protein Conformation Stereochemistry Golgi Apparatus Crystallography X-Ray Biochemistry Hydrophobic effect Structure-Activity Relationship symbols.namesake chemistry.chemical_compound alpha-Mannosidase Mannosidases Animals Humans Structure–activity relationship Moiety Computer Simulation Amines Enzyme Inhibitors Molecular Biology Organic Chemistry Computational Biology Golgi apparatus Swainsonine chemistry symbols Molecular Medicine Drosophila Indicators and Reagents Amine gas treating Lysosomes Protein Binding |
| Zdroj: | ChemBioChem. 5:1220-1227 |
| ISSN: | 1439-4227 |
| DOI: | 10.1002/cbic.200300842 |
| Popis: | Mannostatin and aminocyclopentitetrol analogues with various substitutions at the amino function were synthesized. These compounds were tested as inhibitors of human Golgi and lysosomal alpha-mannosidases. Modification of the amine of mannostatin had only marginal effects, whereas similar modifications of aminocyclopentitetrol led to significantly improved inhibitors. Ab initio calculations and molecular docking studies were employed to rationalize the results. It was found that mannostatin and aminocyclopentitretrol could bind to Golgi alpha-mannosidase II in a similar mode to that of the known inhibitor swainsonine. However, due to the flexibility of the five-membered rings of these compounds, additional low-energy binding modes could be adopted. These binding modes may be relevant for the improved activities of the benzyl-substituted compounds. The thiomethyl moiety of mannostatin was predicted to make favorable hydrophobic interactions with Arg228 and Tyr727 that would possibly account for its greater inhibitory activity. |
| Databáze: | OpenAIRE |
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