title: Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacotherapy & Translational Research, University of Florida, Gainesville, Florida 32610-0486, USA.
authors.forename: Jenna A
authors.initials: JA
authors.lastname: Rhoades
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Peterson
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: David I
authors.initials: DI
authors.lastname: Appel
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004347:Drug Interactions; D005663:Furans; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D019888:Nelfinavir / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology; D019258:Saquinavir / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D005663:Furans; D009842:Oligopeptides; D011480:Protease Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; C095108:amprenavir; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir