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

doi:10.1016/S0014-5793(01)02672-2

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

40 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 (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.

Original language	English (US)
Pages (from-to)	93-97
Number of pages	5
Journal	FEBS Letters
Volume	502
Issue number	3
DOIs	https://doi.org/10.1016/S0014-5793(01)02672-2
State	Published - 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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10.1016/S0014-5793(01)02672-2

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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 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.",

keywords = "Antiviral agent, Computational screening, Cysteine proteinase inhibitor, Development, Drug discovery, In silico screening, Molecular docking, Structure-based drug design",

author = "Pang, {Yuan Ping} and Kun Xu and Kollmeyer, {Thomas M.} and Emanuele Perola and McGrath, {William J.} and Green, {Dave T.} and Mangel, {Walter F.}",

note = "Funding Information: Supported by the Mayo Foundation (Y.-P.P. and T.M.K.), Biocept Inc. (Y.-P.P.), and DARPA (Grant DAAD19-01-1-0322, Y.-P.P.). E.P. was supported by the Istituto Pasteur-Fondazione Cenci Bolognetti. K.X. was supported by an NIH training grant (CA75926) to the Tumor Biology Program of the Mayo Graduate School and by the Mayo Foundation. Research by W.F.M. was supported by the Office of Biological and Environmental Research of the U.S. Department of Energy under Prime Contract DE-AC0298Ch10886 with Brookhaven National Laboratory, and by National Institutes of Health Grant AI41599. ",

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T2 - Steps toward selective, irreversible inhibitors of cysteine proteinases

AU - Pang, Yuan Ping

AU - Xu, Kun

AU - Kollmeyer, Thomas M.

AU - Perola, Emanuele

AU - McGrath, William J.

AU - Green, Dave T.

AU - Mangel, Walter F.

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PY - 2001/8/3

Y1 - 2001/8/3

N2 - 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.

AB - 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.

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KW - In silico screening

KW - Molecular docking

KW - Structure-based drug design

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

Abstract

Keywords

ASJC Scopus subject areas

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