title: Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors.
abstract: Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(l/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substituents, and a smaller one at the C6-beta region.
authors.affiliation: Theoretical Biology and Biophysics Group (T-10), Los Alamos National Laboratory, NM 87545, USA.
authors.forename: T I
authors.initials: TI
authors.lastname: Oprea
authors.forename: A E
authors.initials: AE
authors.lastname: García
mesh_terms: D000735:Androstenedione / Q000737:chemistry / Q000378:metabolism; D047072:Aromatase Inhibitors; D001185:Artificial Intelligence; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D012995:Solubility; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D013256:Steroids; D000735:Androstenedione