Inhibition of cytochrome P450 1B1 (CYP1B1) represents a promising therapeutic strategy, because it would enable action at three different levels: (1) by inhibiting the formation of mutagenic 4-hydroxy-estradiol, (2) by inhibiting the bioactivation of procarcinogens, and (3) by reducing drug-resistance. Surprisingly, few steroids were reported as inhibitors of CYP1B1. From a screening performed with 90 steroid derivatives, we identified thioestrone (B19) as an inhibitor (IC50=3.4μM) of CYP1B1. Molecular modeling studies showed that the 3-SH group of B19 is closer (3.36Å) to the iron atom of the heme system than the 3-OH group of enzyme substrates estrone and estradiol (4.26Å and 3.58Å, respectively). B19 also produced a better docking GOLD score that correlated with the inhibitory results obtained. The estrane derivative B19 represents an interesting lead compound that can be easily modified to extend the structure-activity relationship study and to provide a next generation of more powerful CYP1B1 inhibitors.
Keywords: CYP1B1; Enzyme; Inhibitor; Screening; Steroid.
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