MOLECULAR MODELING OF MAMMALIAN CYP2B ISOFORMS AND THEIR INTERACTION WITH SUBSTRATES, INHIBITORS AND REDOX PARTNERS

1. The construction of three-dimensional models of CYP2B isozymes from rat (CYP2B1), rabbit (CYP2B4) and man (CYP2B6), based on a multiple s equence alignment with CYP102, a unique eukaryotic-like bacterial P450 (in terms of possessing an NADPH-dependent FAD- and FMN-containing ox idoreductase redox partner) of known crystal structure, is reported. 2 . The enzyme models described are shown to be consistent with experime ntal evidence from site-directed mutagenesis studies, antibody recogni tion sites and amino acid residues identified as being associated with redox partner interactions, together with the location of a key serin e residue (Ser-128) likely to be involved in protein kinaseA-mediated phosphorylation. 3. A substantial number of known substrates and inhib itors of CYP2B isozymes are shown to fit the putative active sites of the enzyme models in agreement with their reported position of metabol ism or mode of inhibition respectively. In particular, there is comple mentarity between the characteristic non-planar geometries of CYP2B su bstrates and key groups in the enzymes' active sites. 4. Molecular mod elling of CYP2B isozymes appears to rationalize a number of the report ed findings from quantitative structure-activity relationship investig ations on series of CYP2B substrates and inhibitors.