Targeting Overexpressed Aromatase in Estrogen Positive Human Cancers: Isorottlerin Emerged as Potential Inhibitor of Aromatase in Computational Docking and Dynamics Simulation Study

Abstract

Background: Aromatase enzyme activity is a key step in the biosynthesis of estrogens. Aromatase is a monooxygenase coded by gene CYP19A1 which catalysis myriad biological reactions associated with the biosynthesis of steroids. Over expression of aromatase is routinely observed in estrogen-responsive breast cancer cells of postmenopausal women. Aromatase inhibitors such as anastrozole, exemestane and letrozole are predominantly utilized to treat these hormone dependent breast cancers. However, drug resistance and side effects are commonly associated in such treatments.Objective: The present study investigates the inhibitory activity of isorottlerin (a novel Mallotus philippinensis derived flavanone) compared against known aromatase kinase inhibitors, namely anastrozole, exemestane and letrozole.Methods: Anastrozole, exemestane and letrozole together with isorottlerin were docked on human placenta aromatase. The 3D structure of aromatase (PDB id: 3s7s) employed for docking studies using Autodock vina, MGL tools as well as molecular dynamic studies utilizing the iMOD server.Results: Computational studies revealed isorottlerin as a competitive aromatase kinase inhibitor compared against FDA approved drugs, specifically anastrozole, exemestane and letrozole. In addition, docking studies results suggested that similar interactions in the binding site of aromatase. The binding energies of docked anastrozole, exemestane, letrozole and isorottlerin complexes with aromatase kinase were -7.8, -10.7, -8.4 and -11.0 kcal/mol, respectively. The docking results were supported through molecular simulation studies using the iMOD server. Conclusion:The in silico docking simulations of anastrozole, exemestane, letrozole and isorottlerin suggested that isorottlerin is a competitive inhibitor of aromatase kinase.