Modeling the aromatase inhibitor activity of indole-imidazole derivatives: Quantitative structure activity relationship and molecular docking study

Abstract

Aromatase, a cytochrome P450 enzyme complex present in breast tissues, plays a significant role in the biosynthesis of estrogen from androgen. Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. Therefore, inhibition of aromatase is a promising target for hormone-dependent breast cancer therapy. In this study in order to obtain the structure requirements for the inhibition of the active sites of aromatase enzyme, the quantitative structure-activity relationships(QSAR) of 19 indole-imidazole derivatives was investigated by the PLS method. The dataset was split randomly into training set (15 compounds) to build the QSAR model and test set (3 compounds) for the external validation of the model. As a result, a model with only three descriptors (diameter, petitjean, Q_VSA_FPNEG) was found to be robust enough for prediction of the aromatase inhibitor activity of the new designed indole-imidazole derivatives, with an R2 of 0.892 and Q2 of 0.741. A series of a new 112 compounds were modeled and designed,out of these, only 18 compounds were found to have biological activity more than those of letrozole (reference compound); these compounds were docked into the active site of aromatase to understand their inhibition action and their binding energy toward aromatase enzyme. Analysis of energy of the eighteen compound-aromatase complexes revealed that compound CVIII has a low binding energy (strong binding affinity) to the aromatase as compared to letrozole; the energy of this compound is less by 8 units than those of letrozole, this compound is enhanced by electron withdrawing group (COOH) at meta position of the phenyl ring of indole.