Simulation, 3D-QSAR, molecular docking and pharmacophore mapping studies on indole derivatives as aromatase inhibitors

Aromatase inhibition is a proven strategy for the treatment of ER+ breast cancer, which accounts for more than 70 % of cases of breast cancer. Indole-based aromatase inhibitors have changed the dynamics of anti-breast cancer drug discovery with efficacy in the nanomolar range. In the present research, we have employed a combination of molecular docking studies, SOMFA-based 3D-QSAR investigations, Pharmacophore mapping, and MD-simulation studies (100 ns) to identify the binding modes as well as to map key pharmacophoric features of indole derivatives to target aromatase. Molecular docking studies showed that the most potent compound, 4 , fits into the binding pocket of aromatase with superior binding affinity compared to letrozole. The SOMFA-based 3D-QSAR model effectively predicted activity using shape and electrostatic potential fields. Pharmacophore mapping results indicated that one hydrogen bond acceptor (A) and three aromatic rings (R) are essential for optimum aromatase inhibitory activity. MD simulation studies confirmed the stable binding of compound 4 in the binding pocket of aromatase. The designed compound S8 exhibited the predicted pIC 50 value of 0.719 nM, which is comparable to that of the most active compound 4. These findings may be used by medicinal chemists for the development of new indole-based aromatase inhibitors for the treatment of ER+ breast cancer.