Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

ISSN: 1873-5294 (Online)
ISSN: 1568-0266 (Print)


Volume 14, 24 Issues, 2014


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Current Topics in Medicinal Chemistry

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  • 11th of 58 in Chemistry, Medicinal



Editor-in-Chief:
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Fox Chase Chemical Diversity Center, Inc
Doylestown, PA
USA


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Ritonavir Analogues as a Probe for Deciphering the Cytochrome P450 3A4 Inhibitory Mechanism

Author(s): Irina F. Sevrioukova and Thomas L. Poulos

Affiliation: University of California Irvine, Department of Molecular Biology and Biochemistry, 3205 McGaugh Hall, Irvine, California 92697-3900, USA.

Abstract

Inactivation of human drug-metabolizing cytochrome P450 3A4 (CYP3A4) could lead to serious adverse events such as drug-drug interactions and toxicity. However, when properly controlled, CYP3A4 inhibition may be beneficial as it can improve clinical efficacy of co-administered therapeutics that otherwise are quickly metabolized by CYP3A4. Currently, the CYP3A4 inhibitor ritonavir and its derivative cobicistat are prescribed to HIV patients as pharmacoenhancers. Both drugs were designed based on the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To unravel the structural basis of CYP3A4 inhibition, we compared the binding modes of ritonavir and ten analogues using biochemical, mutagenesis and x-ray crystallography techniques. This review summarizes our findings on the relative contribution of the heme-ligating moiety, side chains and the terminal group of ritonavir-like molecules to the ligand binding process, and highlights strategies for a structure-guided design of CYP3A4 inactivators.




Keywords: Crystal structure, CYP3A4, inhibitor design, ligand binding, pharmacophore, ritonavir analogues.

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Article Details

Volume: 14
Issue Number: 11
First Page: 1348
Last Page: 1355
Page Count: 8
DOI: 10.2174/1568026614666140506120647
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