title: Discovery of a new inhibitor lead of adenovirus proteinase: steps toward selective, irreversible inhibitors of cysteine proteinases.
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 microM) 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.
authors.affiliation: Mayo Clinic Cancer Center, Mayo Foundation for Medical Education and Research, Rochester, MN 55905, USA. pang@mayo.edu
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
authors.forename: K
authors.initials: K
authors.lastname: Xu
authors.forename: T M
authors.initials: TM
authors.lastname: Kollmeyer
authors.forename: E
authors.initials: E
authors.lastname: Perola
authors.forename: W J
authors.initials: WJ
authors.lastname: McGrath
authors.forename: D T
authors.initials: DT
authors.lastname: Green
authors.forename: W F
authors.initials: WF
authors.lastname: Mangel
mesh_terms: D000260:Adenoviruses, Human / Q000201:enzymology*; D000818:Animals; D002417:Cattle; D003545:Cysteine / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005449:Fluorenes / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010206:Papain / Q000187:drug effects; D011994:Recombinant Proteins / Q000302:isolation & purification
chemical_list: C437168:2,4,5,7-tetranitro-9-fluorenone; D015853:Cysteine Proteinase Inhibitors; D005449:Fluorenes; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; D010206:Papain; C091827:adenain; D003545:Cysteine