A novel molecular modelling technique, namely the substrate-heme complex (SHC) approach, is used to derive a representation of the overall active site of the enzyme complex 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase), a cytochrome P-450 dependent enzyme involved in the oxidative hydroxylation of the C(17) and cleavage of the C(17)-C(20) bond of the progestins (e.g., progesterone or pregnenolone). Using the derived model, we have rationalised the inhibitory activity of a number of steroidal and non-steroidal inhibitors, including miconazole and ketoconazole (the latter being a former potential treatment of hormone-dependent prostate cancer). (C) 2004 Elsevier Inc. All rights reserved.