Investigations on inhibitors of human 17α-hydroxylase-17,20-lyase and their interactions with the enzyme -: Molecular modelling of 17α-hydroxylase-17,20-lyase, part II

New methods in treatment of hormone-dependent diseases like prostate or breast cancer have become a major subject in medical and pharmaceutical research. Because of the direct correlation of cancer growth and hormone concentration, inhibition of hormone biosynthesis presents a promising strategy in cancer therapy. The key enzyme in androgen biosynthesis is the 17 alpha -hydroxylase-17,20-lyase a cytochrome P450 system, which specifically converts gestagens to androgens. Because the 3D-structure of the enzyme is still unknown most recently a ligand-based design was used to gain deeper insights into protein structure and function. In this paper we present molecular modelling studies on compounds acting as competitive inhibitors of the hurnan 17 alpha -hydroxylase-17,20-lyase. The compounds developed by Hartmann et al. belong to two different structural classes and show a wide range of inhibitory potency. The physico-chemical properties of the molecules were investigated and compared by studying structural flexibility and by calculating molecular interactions fields. The superimposition of all inhibitors in a low energy conformation yielded in the common pharmacophore. In the second part of the paper individual inhibitors were docked into the active site of the enzyme model of CYP17 developed in our group. The dynamic behaviour and stability of the protein-inhibitor-complexes was studied. The protein ligand interactions observed in course of the molecular dynamics simulations correspond well with the experimental data.