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

European Journal of Medicinal Chemistry
Shuchi Nagar, Achintya Saha

Abstract

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(pred)(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).

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