Pharmacophore Based 3D-QSAR Study of Biphenyl Derivatives as Nonsteroidal Aromatase Inhibitors in JEG-3 Cell Lines

Lakshmi   Narayana   Bheemanapalli; Balakumar      C; Venkat   Rao   Kaki; Rajwinder      Kaur; Raghuram   Rao   Akkinepally

Abstract

Breast cancer is one of the most high-profile malignant diseases in modern society. Among postmenopausal women affected by the disease, a substantial portion has breast tumors that are estrogen-receptor positive. A common therapeutic intervention for this type of cancer is through endocrine therapy. Endocrine agents can act by either diminishing the availability or inhibiting the binding of estrogens to ER. Aromatase catalyzes the conversion of androgens to estrogens in the final step of the biosynthesis of estrogens and is therefore an attractive therapeutic target for inhibition. 3DQSAR pharmacophore modeling studies were undertaken for biphenyl derivatives as aromatase inhibitors in JEG-3 cell lines. A four-point pharmacophore with two H-bond acceptors and two aromatic rings as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R² = 0.977 for training set molecules. The generated model showed excellent predictive power, with a correlation coefficient of Q² = 0.946 for an external test set. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may help in the design and development of potent biphenyl derivatives as new aromatase inhibitors.

Keywords: Biphenyl derivatives, docking, 3D-QSAR, JEG-3 cell lines, nonsteroidal aromatase inhibitors, pharmacophore mapping.

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