Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 497, Issue 1-2, Pages 68-81Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2010.03.011
Keywords
P450; Metabolic stability; Type II binding; 3A4
Categories
Funding
- National Institute of General Medical Sciences [GM84546]
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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. (C) 2010 Elsevier Inc. All rights reserved.
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