A MOLECULAR-MODEL FOR THE INTERACTION BETWEEN VOROZOLE AND OTHER NONSTEROIDAL INHIBITORS AND HUMAN CYTOCHROME-P450 19 (P450 AROMATASE)

In a previous study (Vanden Bossche et al., Breast Cancer Res. Treat. 30 (1994) 43) the interaction between (+)-S-vorozole and the I-helix of cytochrome P450 19 (P450 aromatase) has been reported. In the present study we extended the ''I-helix model'' by incorporating the C-terminus of P450 aromatase. The crystal structures of P450 101 (P450 cam), 102 (P450 BM-3) and 108 (P450 terp) reveal that the C-terminus is structurally conserved and forms part of their respective substrate binding pocket. Furthermore, the present study is extended to the interaction between P450 aromatase and its natural substrate androstenedione and the non-steroidal inhibitors (-)-R-vorozole, (-)-S-fadrozole, R-liarozole and (-)-R-aminoglutethimide. It is found that (+)-S-vorozole, (-)-S -fadrozole and R-liarozole bind in a comparable way to P450 aromatase and interact with both the I-helix (Glu(302) and Asp(309)) and C-terminus (Ser(478) and His(480)). The weak activity of (-)-R-aminoglutethimide might be attributed to a lack of interaction with the C-terminus.