Investigations on inhibitors of human 17 alpha-hydroxylase-17,20-lyase andtheir interactions with the enzyme - Molecular modelling of 17 alpha-hydroxylase-17,20-lyase, part II

New methods in treatment of hormone-dependent diseases like prostate or bre ast cancer have become a major subject in medical and pharmaceutical resear ch. Because of the direct correlation of cancer growth and hormone concentr ation, inhibition of hormone biosynthesis presents a promising strategy in cancer therapy. The key enzyme in androgen biosynthesis is the 17 alpha -hy droxylase-17,20-lyase a cytochrome P450 system, which specifically converts gestagens to androgens. Because the 3D-structure of the enzyme is still un known most recently a ligand-based design was used to gain deeper insights into protein structure and function. In this paper we present molecular mod elling studies on compounds acting as competitive inhibitors of the hurnan 17 alpha -hydroxylase-17,20-lyase. The compounds developed by Hartmann et a l. belong to two different structural classes and show a wide range of inhi bitory potency. The physico-chemical properties of the molecules were inves tigated and compared by studying structural flexibility and by calculating molecular interactions fields. The superimposition of all inhibitors in a l ow energy conformation yielded in the common pharmacophore. In the second p art 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 liga nd interactions observed in course of the molecular dynamics simulations co rrespond well with the experimental data.