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

Using the computer docking program EUDOC, in silico screening of a chemical database for inhibitors of human adenovirus cysteine proteinase (hAVCP) id entified 2,4,5,7-tetranitro-9-fluorenone that selectively and irreversibly inhibits hAVCP in a two-step reaction: reversible binding (K-i = 3.09 muM) followed by irreversible inhibition (k(i) = 0.006 s(-1)). The reversible bi nding is due to molecular complementarity between the inhibitor and the act ive site of hAVCP, which confers the selectivity of the inhibitor. The irre versible inhibition is due to substitution of a nitro group of the inhibito r by the nearby Cys122 in the active site of hAVCP. These findings suggest a new approach to selective, irreversible inhibitors of cysteine proteinase s involved in normal and abnormal physiological processes ranging from embr yogenesis to apoptosis and pathogen invasions. (C) 2001 Published by Elsevi er Science B.V. on behalf of the Federation of European Biochemical Societi es.