MOLECULAR MODELING OF CYP3A4 FROM AN ALIGNMENT WITH CYP102 - IDENTIFICATION OF KEY INTERACTIONS BETWEEN PUTATIVE ACTIVE-SITE RESIDUES AND CYP3A-SPECIFIC CHEMICALS

1. A structural model of CYP3A4 is reported on the basis of a novel am ino acid sequence alignment between the CYP3 family and CYP102, a bact erial P450 of known crystal structure. 2. Construction of the CYP3A4 m odel from CYP102 is facilitated by the relatively high sequence homolo gy between the two proteins (52 % homology; 27 % identity) with many c onservative amino acid changes, yielding a structure of low internal e nergy. 3. A considerable number of specific substrates, and some speci fic inhibitors, are shown to occupy the putative CYP3A4 active site vi a interactions with the same amino acid residues in almost all cases i nvestigated. 4. The CYP3A4 model rationalizes the known positions of m etabolism for many substrates of this major human P450 such that the r oute of metabolism in novel development compounds can be predicted.