Rhoades_2012_Pharm.Res_29_972

Reference

Title : Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions - Rhoades_2012_Pharm.Res_29_972
Author(s) : Rhoades JA , Peterson YK , Zhu HJ , Appel DI , Peloquin CA , Markowitz JS
Ref : Pharm Res , 29 :972 , 2012
Abstract : PURPOSE: To predict and determine whether the protease inhibitors (PIs) nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir could serve as metabolic inhibitors of the human CES1 (hCES1) using both molecular modeling techniques and in vitro inhibition assays. METHODS: Initially, a molecular modeling approach was utilized to predict whether the selected PIs could serve as hCES1 inhibitors. The inhibitory effects of these PIs on hCES1 activity were then further evaluated utilizing previously established in vitro assay. RESULTS: Pharmacophore and 2D-QSAR modeling predicted that nelfinavir would serve as a potent hCES1 inhibitor. This hypothesis was validated by in vitro hCES1 inhibition studies. Other PIs (amprenavir, atazanavir, ritonavir, saquinavir) were evaluated and also shown to be hCES1 inhibitors in vitro, although substantially less potent relative to nelfinavir. CONCLUSION: Computational molecular modeling is a valid approach to identify potential hCES1 inhibitors as candidates for further assessment using validated in vitro techniques. DDIs could occur when nelfinavir is co-administered with drugs metabolized by hCES1.
ESTHER : Rhoades_2012_Pharm.Res_29_972
PubMedSearch : Rhoades_2012_Pharm.Res_29_972
PubMedID: 22161308

Related information

Citations formats

Rhoades JA, Peterson YK, Zhu HJ, Appel DI, Peloquin CA, Markowitz JS (2012)
Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions
Pharm Res 29 :972

Rhoades JA, Peterson YK, Zhu HJ, Appel DI, Peloquin CA, Markowitz JS (2012)
Pharm Res 29 :972

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    [paper] => Rhoades_2012_Pharm.Res_29_972
    [author] => Rhoades JA || Peterson YK || Zhu HJ || Appel DI || Peloquin CA || Markowitz JS
    [year] => 2012
    [title] => Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions
    [journal] => Pharm Res
    [volume] => 29
    [page] => 972
    [medline] => 22161308
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            [content] => PURPOSE: To predict and determine whether the protease inhibitors (PIs) nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir could serve as metabolic inhibitors of the human CES1 (hCES1) using both molecular modeling techniques and in vitro inhibition assays. METHODS: Initially, a molecular modeling approach was utilized to predict whether the selected PIs could serve as hCES1 inhibitors. The inhibitory effects of these PIs on hCES1 activity were then further evaluated utilizing previously established in vitro assay. RESULTS: Pharmacophore and 2D-QSAR modeling predicted that nelfinavir would serve as a potent hCES1 inhibitor. This hypothesis was validated by in vitro hCES1 inhibition studies. Other PIs (amprenavir, atazanavir, ritonavir, saquinavir) were evaluated and also shown to be hCES1 inhibitors in vitro, although substantially less potent relative to nelfinavir. CONCLUSION: Computational molecular modeling is a valid approach to identify potential hCES1 inhibitors as candidates for further assessment using validated in vitro techniques. DDIs could occur when nelfinavir is co-administered with drugs metabolized by hCES1.
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