Exploring benzcyclo derivatives as potent aromatase inhibitors using ligand-based modeling studies

Aromatase inhibition is an attractive strategy for the treatment of hormone-dependent breast cancer. Quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies are performed on benzcyclo- pentane/hexane derivatives to generate statistically significant models. Linear free energy QSAR model (R-2 = 0.874, Q(2) = 0.824, R(pred)2 = 0.757) showed the importance of hydrophobicity and atomic charge functionality of the molecule for the activity. 3D QSAR models generated with molecular field (CoMFA, R-2 = 0.973, Q(2) = 0.702, R-pred(2) = 0.612) and similarity analysis (CoMSIA, R-2 = 0.976, Q(2) = 0.803, R-red(2) = 0.706) studies indicated the importance of electrostatic and steric fields along with hydrophobicity of the molecule as important features for inhibiting aromatase enzyme. Further pharmacophore space modeling study (Q(2) = 0.845, R-pred(2) = 0.648) confirmed that molecular hydrophobicity plays key role for aromatase inhibition. The structure function characterization is adjudged in the active site of the target (3EQM). (C) 2010 Elsevier Masson SAS. All rights reserved.