Background: Tobacco smoking is a leading cause of preventable disease and death globally.
Nicotine is the main addictive component in tobacco. Nicotine is eliminated from the body by
biotransformation in the liver to inactive metabolites. This reaction is catalyzed by the cytochrome
P450 2A6 (CYP2A6) enzyme. Administering chemical inhibitors of CYP2A6 has been shown to slow
down the elimination of nicotine with consequent reduction in number of cigarettes smoked. We have
systematically developed small molecule CYP2A6 inhibitors with good balance between potency and
Objective: During this process we have noticed that many potent CYP2A6 inhibitors also inhibit other human liver CYP
forms, most notably CYP1A2 and CYP2B6. This study aimed at defining common and distinct features of ligand binding
to CYP1A2, CYP2A6 and CYP2B6 active sites.
Methods: We used our previous chemical inhibitor databases to construct improved 3-dimensional quantitative structureactivity
relationship (3D-QSAR) models for CYP1A2, CYP2A6 and CYP2B6.
Results: Combined 3D-QSAR and docking procedures yielded precise information about the common and distinct interactions of
inhibitors and the enzyme active sites. Positioning of hydrogen bond donor/acceptor atoms and the shape and volume of the
compound defined the potency and specificity of inhibition. A novel potent and selective CYP1A2 inhibitor was found.
Conclusion: This in silico approach will provide a means for very rapid and high throughput prediction of cross-inhibition
of these three CYP enzymes.