Chemical Proteomic Tool for Ligand Mapping of CYP Antitargets: An NMR‐Compatible 3D QSAR Descriptor in the Heme‐Based Coordinate System.

Abstract

Chemical proteomic strategies strive to probe and understand protein−ligand interactions across gene families. One gene family of particular interest in drug and xenobiotic metabolism are the cytochromes P450 (CYPs), the topic of this article. Although numerous tools exist to probe affinity of CYP−ligand interactions, fewer exist for the rapid experimental characterization of the structural nature of these interactions. As a complement to recent advances in X-ray crystallography, NMR methods are being developed that allow for fairly high throughput characterization of protein−ligand interactions. One especially promising NMR approach involves the use of paramagnetic induced relaxation effects to measure distances of ligand atoms from the heme iron in CYP enzymes. Distances obtained from these T1 relaxation measurements can be used as a direct source of 1-dimensional structural information or to restrain a ligand docking to generate a 3-dimensional data set. To facilitate such studies, we introduce the con...