Molecular modeling of human cytochrome P450 2W1 and its interactions with substrates

The human cytochrome P450 2W1 (CYP2W1) was categorized into the so-called "orphan" CYPs because of its unknown enzymatic function. However, recent studies showed that the recombinant CYP2W1 exhibited broad catalytic activity towards several chemicals. Furthermore, this enzyme was selectively expressed in some forms of cancers, whereas a very low expression was found in human normal issues. These render CYP2W1 as a potential drug target for cancer therapy. At present, however, little information is available on the active site topology and the substrate binding modes of CYP2W1. In this study, the three-dimensional model of CYP2W1 was constructed using the homology modeling method. Two known substrates, benzphetamine and indole, were then docked into the active site, and refined by molecular dynamics simulations. The interaction energy between the substrates and the enzyme was calculated and analyzed by using the MM-GBSA method. The results indicated that the constructed CYP2W1 model can account for the regioselectivity of this enzyme towards the known substrates and van der Waals interactions were the driving force for the substrate binding. Several key residues were identified to be responsible for the binding of indole and benzphetamine with CYP2W1. These findings provide useful information for the detailed characterization of the biological roles of CYP2W1 and structure-based drug design of this enzyme.