Journal article
Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance
Drug metabolism and disposition, Vol.43(1), pp.34-41
01/2015
Handle:
https://hdl.handle.net/2376/103471
PMCID: PMC4279085
PMID: 25326286
Abstract
The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450-mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O(6)-benzylguanine. Based on the estimated IC50 (<100 μM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26-73 and 0.80-120 μM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme-inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r(2) = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance-drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation.
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- Title
- Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance
- Creators
- John T Barr - Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)Jeffrey P Jones - Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)Nicholas H Oberlies - Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)Mary F Paine - Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.) mary.paine@wsu.edu
- Publication Details
- Drug metabolism and disposition, Vol.43(1), pp.34-41
- Academic Unit
- Chemistry, Department of; Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- R01 GM100874 / NIGMS NIH HHS R01-GM077482 / NIGMS NIH HHS R01-GM100874 / NIGMS NIH HHS R01 GM077482 / NIGMS NIH HHS
- Identifiers
- 99900546541601842
- Language
- English
- Resource Type
- Journal article