Journal article
The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4
Archives of biochemistry and biophysics, Vol.497(1), pp.68-81
2010
Handle:
https://hdl.handle.net/2376/116209
PMCID: PMC2864005
PMID: 20346909
Abstract
One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound’s metabolic stability can be increased by incorporation of a sp
2 nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme-iron (termed type II binding). However, questions regarding binding affinity, metabolic stability, and how metabolism of type II binders occurs remain unanswered. Herein, we use pyridinyl quinoline-4-carboxamide analogs to answer these questions. We show that type II binding can have a profound influence on binding affinity for CYP3A4, and the difference in binding affinity can be as high as 1200-fold. We also find that type II binding compounds can be extensively metabolized, which is not consistent with the dead-end complex kinetic model assumed for type II binders. Two alternate kinetic mechanisms are presented to explain the results. The first involves a rapid equilibrium between the type II bound substrate and a metabolically oriented binding mode. The second involves direct reduction of the nitrogen-coordinated heme followed by oxygen binding.
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Details
- Title
- The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4
- Creators
- Chi-Chi Peng - Department of Chemistry, Washington State University, P.O. Box 644630, Fulmer 455, Pullman, WA 99164-4630, USAJosh T Pearson - Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USADan A Rock - Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USACarolyn A Joswig-Jones - Department of Chemistry, Washington State University, P.O. Box 644630, Fulmer 455, Pullman, WA 99164-4630, USAJeffrey P Jones - Department of Chemistry, Washington State University, P.O. Box 644630, Fulmer 455, Pullman, WA 99164-4630, USA
- Publication Details
- Archives of biochemistry and biophysics, Vol.497(1), pp.68-81
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Inc
- Identifiers
- 99900548107701842
- Language
- English
- Resource Type
- Journal article