Virtual screening and molecular docking study of alpha-naphthoflavone analogs as cytochromes P450-1A1 inhibitors

Cytochromes P450 (CYP450) inhibitors are compounds that inhibit CYP450 enzyme activity. CYP450 inhibitors can be used to manipulate the metabolism of certain drugs to achieve desired therapeutic. Flavonoids, including alpha-flavones, are known to have a wide range of biological activities and are of interest as potential therapeutics for various diseases. Several chemicals have been synthesized from the alpha-flavone scaffold that has been found to have inhibitory effects on the CYP450-1A1 enzyme system. Therefore, synthesizing chemicals from the alpha flavone scaffold and studying their inhibitory effects on the CYP450-1A1 enzyme system can lead to the discovery of drug candidates that selectively inhibit certain CYP450-1A1 enzymes. Quantitative Structure-Activity Relationship (QSAR) and molecular docking can be used to predict the IC₅₀ of CYP450-1A1 inhibitors. The pIC₅₀ mean value of 323 compounds known as CYP450 inhibitors were used as training datasets. The 30 alpha-naphthoflavone analogs built from the alpha-naphthoflavone scaffold were studied for their inhibition activity using linear and nonlinear regression. Among 30 compounds, 19 compounds potentially have CYP450-1A1 inhibition activity. Among 19 predicted active compounds, three compounds have IC₅₀ below 50 nM. The QSAR regression models predict IC₅₀ of 10-bromo-1-phenyl-phenanthrene (compound 0), 1-phenylthioxanthen-9-one (compound 6), and 2-bromo-1-phenyl-phenanthrene (compound 29) which were 36.9173, 44.8891, 36.9173 nM. The binding energies between these three compounds with chains A, B, C, and D of CYP450-1A1 were below -10 kc/mol. Thus, the interactions between these three compounds with CYP450-1A1 were significant. Consideration from QSAR and molecular docking results might be relevant in the optimization of alpha-naphthoflavone analogs' potential as CYP450-1A1 inhibitors.