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

FEBS Letters

Xu, Kun⁴  Kollmeyer, Thomas M.¹  Green, Dave T.³  Mangel, Walter F.³  McGrath, William J.³  Perola, Emanuele¹  Pang, Yuan-Ping² 

[1] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, MN 55905, USA;Mayo Clinic Cancer Center, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, MN 55905, USA;Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA;Tumor Biology Program, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, MN 55905, USA

关键词: Computational screening;    In silico screening;    Structure-based drug design;    Molecular docking;    Antiviral agent;    Cysteine proteinase inhibitor;    Drug discovery;    Development;   

DOI  :  10.1016/S0014-5793(01)02672-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown