Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

  • Irina F. SevrioukovaEmail author
  • Thomas L. Poulos
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 851)


Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug-drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies.


Cytochrome P450 CYP3A4 Ligand binding Enzyme inhibition Drug metabolism Drug-drug interactions 



Financial support from the National Institute of General Medical Sciences (Grant GM57353) and the California Center for Antiviral Drug Discovery is gratefully appreciated.


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineUSA
  2. 2.Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical SciencesUniversity of CaliforniaIrvineUSA

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