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Discovery of a new inhibitor lead of adenovirus proteinase: steps toward selective, irreversible inhibitors of cysteine proteinases
Author(s) -
Pang Yuan-Ping,
Xu Kun,
Kollmeyer Thomas M.,
Perola Emanuele,
McGrath William J.,
Green Dave T.,
Mangel Walter F.
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02672-2
Subject(s) - cysteine , chemistry , active site , biochemistry , cysteine proteinase inhibitors , in silico , binding site , docking (animal) , enzyme , enzyme inhibitor , cystatin , apoptosis , caspase , gene , programmed cell death , cystatin c , medicine , nursing , renal function
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 ( K i =3.09 μM) followed by irreversible inhibition ( k i =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.