Abstract
Cytochromes P450 (P450s) play a major role in the clearance of drugs, toxins and environmental pollutants. In addition, metabolism by P450s can result in toxic or carcinogenic products. The metabolism of pharmaceuticals by P450s is a major concern during the design of new drug candidates. Determining the interactions between P450s and compounds of very diverse structures is complicated by the variability in P450–ligand interactions. Understanding the protein structural elements and the chemical attributes of ligands that dictate their orientation in the P450 active site will aid the development of effective and safe therapeutic agents. The goal of this review is to describe P450–ligand interactions from two perspectives. The first is the various structural elements that microsomal P450s have at their disposal to assume the different conformations observed in x-ray crystal structures. The second is P450–ligand dynamics analyzed by NMR relaxation studies.
Financial & competing interests disclosure
Studies in the authors’ laboratory described in this paper are supported by NIH grants ES003619 and ES006676 to James R Halpert. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.