Autori: Oprea, Tudor I.; Garcia, Angel E.

Editorial: J. Comput.-Aided Mol. Des., 10(3), p.186-200, 1996.

Rezumat:

Inhibition of aromatase, a cytochrome P 450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quant. structure-activity relationship (3D QSAR) method known as Comparative Mol. Field Anal., 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 refs. cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K1), with an explained variance r2 of 0.85, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12(1993Z)9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compds. (repeated 25 times), the q2 for one component was 0.62 and 0.61, resp., while r2 was 0.674. We demonstrate that the predictive r2 based on the index gives a more accurate est. of external predictivity. Using CoMFA, the obsd. differences in aromatase inhibition among C6-substituted steroids are rationalized at the at. level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compds. 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.

Cuvinte cheie: Anti-cancer compounds, Aromatase, CoMFA, QSAR (structure-activity relationships), Steroids,