Journal article
Modeling and synthesis of novel tight-binding inhibitors of cytochrome P450 2C9
Bioorganic & medicinal chemistry, Vol.16(7), pp.4064-4074
2008
Handle:
https://hdl.handle.net/2376/103017
PMID: 18255300
Abstract
Proposed binding modes of inhibitory analogs would lead to an interaction of the phenolate anion with a water molecule stabilized by Ala 297.
Cytochrome P450 2C9 (2C9) is one of the three major drug metabolizing cytochrome P450 enzymes in human liver. Although the crystal structure of 2C9 has been solved, the important physicochemical properties of substrate–enzyme interactions remain difficult to be determined. This is due in part to the conformational flexibility of mammalian P450 enzymes. Therefore, probing the active-site with high-affinity substrates is important in further understanding substrate–enzyme interactions. Three-dimensional quantitative structure–activity relationships (3D-QSAR) and docking experiments have been shown to be useful tools in correlating biological activity with structure. In particular we have previously reported that the very tight-binding inhibitor benzbromarone can provide important information about the active-site of 2C9. In this study we report the binding affinities and potential substrate–enzyme interactions of 4H-chromen-4-one analogs, which are structurally similar to benzbromarone. The chromenone structures are synthetically accessible inhibitors and give inhibition constants as low as 4.2
nM, comparable with the very tightest-binding inhibitors of 2C9. Adding these compounds to our previous 2C9 libraries for CoMFA models reinforces the important electrostatic and hydrophobic features of substrate binding. These compounds have also been docked in the 2C9 crystal structure and the results indicate that Arg 108 plays significant roles in the binding of chromenone substrates.
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Details
- Title
- Modeling and synthesis of novel tight-binding inhibitors of cytochrome P450 2C9
- Creators
- Chi-Chi Peng - Department of Chemistry, Washington State University, PO Box 644630, Pullman, WA 99164-4630, USATom Rushmore - Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USAGregory J Crouch - Department of Chemistry, Washington State University, PO Box 644630, Pullman, WA 99164-4630, USAJeffrey P Jones - Department of Chemistry, Washington State University, PO Box 644630, Pullman, WA 99164-4630, USA
- Publication Details
- Bioorganic & medicinal chemistry, Vol.16(7), pp.4064-4074
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900546549401842
- Language
- English
- Resource Type
- Journal article