Synthesis and evaluation of the antagonistic activity of 3-acetyl-2H-benzo[g]chromen-2-one against mutant Y537S estrogen receptor alpha via E-Pharmacophore modeling, molecular docking, molecular dynamics, and in-vitro cytotoxicity studies

Acquired resistance to classical therapy in patients with estrogen receptor alpha (ER alpha) positive breast cancer is caused by mutations in the ligand-binding domain of ER alpha. One such mutation that is aggressive than other mutations is Y537S occurring at the N-terminal region of helix 12. To tailor a drug with specificity and efficacy against Y537S mutation is the need of the hour. Based on the knowledge that inhibitory activity against mutations works in a ligand-dependent manner i.e. different ligands induce inhibition through various mechanisms. We in our work focused on the inhibitory activity of coumarins against Y537S mutation. In this regard, we employed a methodology using computational molecular modeling and experimental techniques to understand the mechanism by which coumarin induce inhibition. We used computational molecular modeling techniques like E-pharmacophore modeling, molecular docking, and molecular dynamics on synthesized coumarins and studied their in-vitro cytotoxicity studies. From our study, we empathize that coumarins behave as a partial antagonist and understand the mechanism by which it induces partial antagonism. Thus coumarin scaffold can be used effectively in developing a mutant specific drug against Y537S ER alpha. (C) 2020 Elsevier B.V. All rights reserved.