Discovery of a new inhibitor lead of adenovirus proteinase: Steps toward selective, irreversible inhibitors of cysteine proteinases

Yuan Ping Pang, Kun Xu, Thomas M. Kollmeyer, Emanuele Perola, William J. McGrath, Dave T. Green, Walter F. Mangel

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Using the computer docking program EUDOC, in silico screening of a chemical database for inhibitors of human adenovirus cysteine proteinase (hAVCP) identified 2,4,5,7-tetranitro-9-fluorenone that selectively and irreversibly inhibits hAVCP in a two-step reaction: reversible binding (Ki = 3.09 μM) followed by irreversible inhibition (ki = 0.006 s-1). The reversible binding is due to molecular complementarity between the inhibitor and the active site of hAVCP, which confers the selectivity of the inhibitor. The irreversible inhibition is due to substitution of a nitro group of the inhibitor by the nearby Cys122 in the active site of hAVCP. These findings suggest a new approach to selective, irreversible inhibitors of cysteine proteinases involved in normal and abnormal physiological processes ranging from embryogenesis to apoptosis and pathogen invasions.

Original languageEnglish (US)
Pages (from-to)93-97
Number of pages5
JournalFEBS Letters
Volume502
Issue number3
DOIs
StatePublished - Aug 3 2001

Keywords

  • Antiviral agent
  • Computational screening
  • Cysteine proteinase inhibitor
  • Development
  • Drug discovery
  • In silico screening
  • Molecular docking
  • Structure-based drug design

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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