Molecular modelling study of the binding of inhibitors of aromatase to the cytochrome P-450 heme.

A novel molecular modelling study, involving inhibitors bound to a 'substrate-heme complex', is described for steroidal and non-steroidal inhibitors of Aromatase (AR). Results with azole compounds such as CGS-16949A, and its derivatives, agree with recently reported studies that these compounds appear to utilise the steroid C(17) carbonyl binding region of the active site as opposed to the steroid C(3) carbonyl binding region. The study of Aminoglutethimide (AG) type compounds, however, suggests that they mimic the steroid C(17) and not the C(3) carbonyl group as suggested by previous workers. However, results with inhibitors based on pyridine ligands such as 3-(4'-pyridyl)-3-ethyl piperidine-2, 6-dione (PYG), suggest that these compounds utilise the steroid C(3) carbonyl binding region and therefore agrees with previous reports. Consideration of the orientation of the R and S enantiomers of PYG is, however, found to be a reversal of that previously reported. Using inhibitors bound to the 'substrate-heme complex', and data from previous studies of derivatives of androstenedione, reasons for differences in activity of enantiomers of AG, PYG, N-octyl-3-(4'-pyridyl)-3-ethyl piperidine-2, 6-dione, and 10-thiiranylestr-4-ene-3, 17-dione, as well as other potent and less potent inhibitors, are put forward.