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.
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Supplemental Table 1
Table of the activists and physiochemical properties of hCES1 inhibitors. Compounds are ordered according to highest activity in pIC50. (DOCX 115 kb)
Supplemental Table 2
Comparison of the relative importance of the top 20 descriptors for hCES1 2D QSAR models. The importance of weight might lie in that the active site pocket has limited volume, excluding compounds above a given mass. (DOCX 70.4 kb)
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Rhoades, J.A., Peterson, Y.K., Zhu, HJ. et al. 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, 972–982 (2012). https://doi.org/10.1007/s11095-011-0637-9
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DOI: https://doi.org/10.1007/s11095-011-0637-9