Molecular modelling of 17 alpha-hydroxylase-17,20-lyase

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 reveals a promising strategy in ca ncer therapy. The key enzyme of androgen biosynthesis is the cytochrome P45 0 system 17 alpha -hydroxylase-17,20-lyase. To gain deeper insights into th e structure and function of this enzyme, whose crystal structure is still u nknown we present in this paper a theoretical 3D-model of the human 17 alph a -hydroxylase-17,20-lyase. The model was built by homology modelling using the crystal structure of the P450 CYPeryF as a template. After energy mini misation followed by molecular dynamics simulation the refined model exhibi ts reasonable protein geometry and a good protein folding quality. For eval uation of protein stability the structure was subjected to molecular dynami cs in a waterbox under almost physiological conditions using the GROMACS pr ogram. The protein structure and folding remains stable even after 300 ps o f free molecular dynamics simulation. The calculation of interaction fields employing the program GRID was used to characterise the active site of the protein. Subsequent docking studies with the natural substrate pregnenolon e and further molecular dynamics of the protein-substrate-complexes enabled us to propose a putative binding-site for the physiological substrates.