A molecular model for the interaction between vorozole and other non-steroidal inhibitors and human cytochrome P450 19 ( P450 Aromatase)

• Published in: Journal of steroid biochemistry and molecular biology 1995-06, Vol.53 (1), p.191-197
• Main Authors: Koymans, Luc M.H., Moereels, Henri, Bossche, Hugo Vanden
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Androstenedione - metabolism; Antineoplastic agents; Aromatase - chemistry; Aromatase - metabolism; Aromatase Inhibitors; Binding Sites; Biological and medical sciences; General aspects; Humans; In Vitro Techniques; Medical sciences; Models, Molecular; Molecular Sequence Data; Pharmacology. Drug treatments; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Alignment; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/0960-0760(95)00033-V

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 wit the C-terminus.