Gaussian-based 3D-QSAR and Pharmacophore Mapping Studies of Indole Derivatives as Aromatase Inhibitors

Aromatase inhibition is one of the most effective strategy for the treatment of ER+ breast cancer, which accounts for about 70% of breast cancer cases. Indole-based aromatase inhibitors have altered the dynamics of the search for anti-breast cancer drugs with efficacy in nanomolar concentrations. In the present study, we have integrated pharmacophore mapping with Gaussian-based 3D-QSAR analysis to map the essential pharmacophoric features of indole-based aromatase inhibitors, aiming to optimize lead molecules.

Pharmacophore mapping and Gaussian-based 3D-QSAR were integrated to identify the steric and electrostatic features essential for aromatase inhibitory activity.

A Gaussian-based 3D-QSAR model with an r² value of 0.7621 and stability of 0.817 was generated to determine the nature of substitutions essential for optimal biological activity. Pharmacophore mapping results indicated that H-bond Donor (D), a Hydrophobic (H) feature, and three aromatic rings (R) are essential for potent inhibitory activity.

In order to identify important structural characteristics of indole-based aromatase inhibitors, the current study successfully integrated pharmacophore mapping investigations with 3D-QSAR. The designed molecule S1 demonstrated activity comparable to letrozole, with a predicted pIC₅₀ value of 9.332 nM.

The designed compound S1 demonstrated a predicted IC₅₀ value of 9.332 nM, comparable to the most active compound 15 and the standard reference Letrozole. The developed models may be utilized by medicinal chemists for the optimization of new indole-based aromatase inhibitors for the effective treatment of ER+ breast cancer.