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Research ArticleArticle

Characterization of Celecoxib and Valdecoxib Binding to Cyclooxygenase

William F. Hood, James K. Gierse, Peter C. Isakson, James R. Kiefer, Ravi G. Kurumbail, Karen Seibert and Joseph B. Monahan
Molecular Pharmacology April 2003, 63 (4) 870-877; DOI: https://doi.org/10.1124/mol.63.4.870
William F. Hood
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James K. Gierse
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Peter C. Isakson
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James R. Kiefer
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Ravi G. Kurumbail
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Karen Seibert
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Joseph B. Monahan
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Abstract

Two compounds (celecoxib and valdecoxib) from the diarylheterocycle class of cyclooxygenase inhibitors were radiolabeled and used to characterize their binding to cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), several single-point variants of COX-2 (Val523Ile, Tyr355Ala, Arg120Ala, Arg120Gln, Arg120Asn) and one triple-point variant of COX-2 [Val523Ile, Arg513His, Val434Ile (IHI)]. We demonstrate highly specific and saturable binding of these inhibitors to COX-2. Under the same assay conditions, little or no specific binding to COX-1 could be detected. The affinity of [3H]celecoxib for COX-2 (KD = 2.3 nM) was similar to the affinity of [3H]valdecoxib (KD = 3.2 nM). The binding to COX-2 seems to be both rapid and slowly reversible with association rates of 5.8 × 106/M/min and 4.5 × 106/M/min and dissociation rates of 14 × 10−3/min (t1/2 = 50 min) and 7.0 × 10−3/min (t1/2 = 98 min) for [3H]celecoxib and [3H]valdecoxib, respectively. These association rates increased (4- to 11-fold) when the charged arginine residue located at the entrance to the main hydrophobic channel was mutated to smaller uncharged amino acids (Arg120Ala, Arg120Gln, and Arg120Asn). Mutation of residues located within the active site of COX-2 that define a ‘side pocket’ (Tyr355Ala, Val523Ile, IHI) of the main channel had a greater effect on the dissociation rate than the association rate. These mutations, which modified the shape of and access to the ‘side pocket’, affected the binding affinity of [3H]valdecoxib more than that of [3H]celecoxib. These binding studies provide direct insight into the properties and binding constants of celecoxib and valdecoxib to COX-2.

Footnotes

  • Abbreviations:
    COX
    cyclooxygenase
    NSAID
    nonsteroidal anti-inflammatory drug
    DEDTC
    diethyldithiocarbamate
    C10M
    decyl maltoside
    D-PBS
    Dulbecco's phosphate-buffered saline
    PG
    prostaglandin
    IHI
    Val523Ile, Arg 513His, Val434Ile
    • Received October 10, 2002.
    • Accepted December 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (4)
Molecular Pharmacology
Vol. 63, Issue 4
1 Apr 2003
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Research ArticleArticle

Characterization of Celecoxib and Valdecoxib Binding to Cyclooxygenase

William F. Hood, James K. Gierse, Peter C. Isakson, James R. Kiefer, Ravi G. Kurumbail, Karen Seibert and Joseph B. Monahan
Molecular Pharmacology April 1, 2003, 63 (4) 870-877; DOI: https://doi.org/10.1124/mol.63.4.870

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Research ArticleArticle

Characterization of Celecoxib and Valdecoxib Binding to Cyclooxygenase

William F. Hood, James K. Gierse, Peter C. Isakson, James R. Kiefer, Ravi G. Kurumbail, Karen Seibert and Joseph B. Monahan
Molecular Pharmacology April 1, 2003, 63 (4) 870-877; DOI: https://doi.org/10.1124/mol.63.4.870
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