A novel molecular modelling study of inhibitors of the 17α-hydroxylase component of the enzyme system 17α-hydroxylase/17,20-lyase (P-45017α)

The enzyme 17 alpha-hydroxylase/17,20-lyase (P-450(17 alpha)) has recently become the focus of research into the fight against hormone dependent prostate cancer. However, the specific nature of this enzyme, in particular, the dual role of its active site, remains unknown. In our drive to elucidate further information regarding P-450(17 alpha), and in light of our experience of other cytochrome P-450 enzymes, we chose to consider each part of this complex enzyme separately (i.e. the 17 alpha-hydroxylase (17 alpha-OHase) and the 17,20-lyase components). We therefore initiated a series of molecular modelling studies involving the construction of a 'substrate-heme complex' for each of the two components. Here, we consider the construction and use of the complex for the 17 alpha-OHase component of this enzyme. Using this approach, we have successfully considered: the binding of steroidal and non-steroidal reversible inhibitors; the structural features necessary for potent inhibition; and, rationalised the mode of action of a number of compounds whose inhibitory activity has not been previously explained, for example, aminoglutethimide tan inhibitor of another related cytochrome P-450 enzyme, aromatase AR). The study concludes that the ability of the inhibitors of 17 alpha-OHase to undergo polar-polar interaction with the active site and for the compounds to closely mimic the substrate plane is a major factor in determining potency. Factors such as log P (log of the partition coefficient value for the distribution of a compound between octanol and water) would then appear to determine the extent of overall inhibitory activity. Overall, the study suggests that the novel substrate-heme complex approach has provided a good approximation of the 17 alpha-OHase active site and has proved to be a useful tool in drug design and discovery. (C) 1999 Elsevier Science Ltd. All rights reserved.