Molecular modelling of human CYP2E1 by homology with the CYP102 haemoprotein domain: investigation of the interactions of substrates and inhibitors within the putative active site of the human CYP2E1 isoform

1. The construction of a three-dimensional model of human CYP2E1 is reporte d. It is based on homology with the haemoprotein domain of the unusual bact erial P450, CYP102, which is of known crystal structure. 2. Interactive docking of a number of human CYP2E1 substrates is consistent with their known positions of CYP2E1-mediated metabolism, where specific i nteractions with key active site amino acid side-chains appear to rationali ze the binding and orientation of substrate molecules. 3. Amino acid residues within the putative active site of human CYP2E1, inc luding those associated with the binding of substrates and inhibitors, are shown to correspond with those identified by site-directed mutagenesis expe riments conducted on CYP2 family isoforms, and they are known to affect sub strate metabolism regioselectivity. 4. Consequently, it was found that the CYP2E1 active sire exhibits compleme ntarity with the structural characteristics of known substrates and inhibit ors of this enzyme, including their relatively low molecular weights and di sposition of hydrogen bond-forming groups.