期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 520, 期 2, 页码 108-116出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2012.02.018
关键词
Cytochrome P450 3A4; Ritonavir analogs; Enzyme inhibition; Crystal structure
资金
- National Institutes of Health [GM33688]
- Gilead Sciences, Inc.
- California Center for Antiviral Drug Discovery
- United States Government
Ritonavir is a HIV protease inhibitor that also potently inactivates cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme. To better understand the mechanism of ligand binding and to find strategies for improvement of the inhibitory potency of ritonavir. currently administered to enhance pharmacokinetics of other anti-HIV drugs that are quickly metabolized by CYP3A4, we compared the manner of CYP3A4 interaction with the drug and two analogs lacking either the heme-ligating thiazole nitrogen or the entire thiazole group. Based on the kinetic, mutagenesis and structural data, we conclude that: (i) the active site residue Arg212 assists binding of all investigated compounds and, thus, may play a more prominent role in metabolic transformation of xenobiotics than previously thought, (ii) peripheral binding of ritonavir limits the heme coordination rate and complicates the binding kinetics, (iii) association of ritonavir-like type II ligands is driven by heme coordination whereas hydrophobic forces define the binding mode, and (iv) substitution of one phenyl group in ritonavir with a smaller hydrophobic moiety could prevent steric clashing and, hence, increase the affinity and inhibitory potency of the drug. (C) 2012 Elsevier Inc. All rights reserved.
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