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(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).
Nagar
Shuchi
S
Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata-700009, India.
Saha
Achintya
A
D001141:Aromatase / Q000737:chemistry / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001554:Benzene / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006586:Hexanes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010420:Pentanes / Q000737:chemistry; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
D047072:Aromatase Inhibitors; D006586:Hexanes; D008024:Ligands; D010420:Pentanes; C033353:pentane; D001141:Aromatase; D001554:Benzene