Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase

Link:
Autor/in:
Erscheinungsjahr:
2010
Medientyp:
Text
Schlagworte:
  • Riboflavin
  • Flavin Mononucleotide
  • Riboflavin production
  • Light
  • Optogenetics
  • Riboflavin
  • Flavin Mononucleotide
  • Riboflavin production
  • Light
  • Optogenetics
  • Indoles/chemistry
  • Multienzyme Complexes/antagonists & inhibitors
  • Drug Evaluation, Preclinical/methods
  • Antitubercular Agents/chemistry
  • Mycobacterium tuberculosis/enzymology
  • Enzyme Inhibitors/chemistry
  • Molecular Structure
  • Binding Sites
Beschreibung:
  • Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a Ki of 70 μM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π-π stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87.
Lizenz:
  • info:eu-repo/semantics/restrictedAccess
Quellsystem:
Forschungsinformationssystem der UHH

Interne Metadaten
Quelldatensatz
oai:www.edit.fis.uni-hamburg.de:publications/dacdd4ac-40fa-4a40-9fd8-55585b8cd54f