Modeling of diarylalkyl-imidazole and diarylalkyl-triazole derivatives as potent aromatase inhibitors for treatment of hormone-dependent cancer

• Published in: Journal of computational chemistry Vol. 31; no. 12; pp. 2342 - 2353
• Main Authors: Nagar, Shuchi, Saha, Achintya
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2010; Wiley Subscription Services, Inc
• Subjects: Analytical chemistry; Antineoplastic Agents, Hormonal - chemistry; Antineoplastic Agents, Hormonal - pharmacology; aromatase inhibitors; Aromatase Inhibitors - chemistry; Aromatase Inhibitors - pharmacology; Breast cancer; CoMFA; Comparative analysis; Computer Simulation; CoMSIA; Energy Transfer; Enzyme kinetics; Enzymes; Estrogens; Hormone replacement therapy; Hydrogen - chemistry; Imidazoles - chemistry; Imidazoles - pharmacology; Ligands; Models, Chemical; Models, Molecular; Molecular chemistry; Molecular Conformation; Neoplasms - drug therapy; Neoplasms - metabolism; pharmacophore; QSAR; Quantitative Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.21528

Aromatase is an enzyme that catalyzes the final step in the conversion of androgen to estrogen. It has become an attractive target for the treatment of estrogen responsive breast cancer. The study has been focused on designing aromatase inhibitors (AIs) that can be selected as probable drug candidate for the treatment of breast cancer. In the present study, long chain diarylalkyl-imidazole and -triazole scaffolds have been considered for exploring pharmacophores as potent AIs using QSAR (Quantitative SAR) and pharmacophore mapping studies. The model generated in linear free energy QSAR study (R² = 0.905, Q²= 0.885, R² pred₍ts₎ = 0.763) showed the importance of hydrophobicity, size and shape of the molecule, van der Waals surface and hydrogen atom contribution influence the activity. 3D QSAR of comparative molecular field analysis (CoMFA, R²= 0.921, Q² = 0.741, R² pred₍ts₎= 0.583) showed that steric and electrostatic features along with hydrophobicity and electronic charge contribution at C₄ (Fig. 1) influence on the inhibitory activity. Comparative molecular similarity analysis (CoMSIA, R² = 0.874, Q² = 0.716, R² pred₍ts₎ = 0.591) study adjudged the presence of steric, electrostatic and hydrophobic fields together with hydrogen bond (HB) donor and acceptor play significant role in inhibitory activity to aromatase enzyme. Further pharmacophore mapping study (Q² = 0.947, Δcost = 113.171, R² pred₍ts₎ = 0.857) suggested that presence of HB acceptor, hydrophobicity with aromatic ring, and the importance of steric contribution influence on the activity. The critical distances among the features are also important for the inhibitor activity.