title: Molecular modelling study of pyrrolidine-2,5-dione based aromatase inhibitors and other known inhibitors.
abstract: A novel molecular modelling study is described for the fitting of non-steroidal 1-substituted-3-[2'(4"-aminophenyl) alkyl] pyrrolidine-2,5-dione based reversible inhibitors of the Aromatase (AR) enzyme to the natural substrate androstenedione. The study suggests that the 'larger' inhibitors (such as the [2'(4"-aminophenyl)alkyl] pyrrolidine-2,5-dione based compounds), after an initial binding of the phenylamine nitrogen lone pair electrons with the Fe3+ haem of the cytochrome P-450, preferentially utilise the region of the AR active site which would normally bind C(17) = O of the substrate. It is suggested that the conformers needed for inhibition by the larger inhibitors when the C(3) carbonyl binding region is used, are too high in energy-in some cases the relative difference between the C(17) carbonyl binding conformer and the C(3) carbonyl binding conformer was found to be greater than 50 KJ mol-1. The 'smaller' inhibitors, such as Aminoglutethimide (AG) however, are found to preferentially use the C(3) = O binding region of the active site. The modelling of smaller inhibitors has suggested a new parameter, the C(10) to liganding hetero atom distance, which may be considered in the design of further inhibitors. We observe that in the potent inhibitors C(10) to liganding hetero atom distances are comparable to approximately twice the steroid C(10) to C(19) bond length, whilst in the less potent inhibitors, much larger distances are observed.
authors.affiliation: Department of Pharmacy, University of Brighton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
mesh_terms: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011760:Pyrrolidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones