Design and pharmacophoric identification of flavonoid scaffold‐based aromatase inhibitors

Abstract

Aromatase is a crucial enzyme for the catalysis of aromatization reaction at the last and rate‐limiting step involved in the conversion of androgenic substrates to an estrogenic substrate. A hormone‐dependent breast cancer in postmenopausal woman can be cured by inhibition of estrogen biosynthesis by the help of aromatase inhibitors (AIs). The mode of interactions of flavonones with the active site of aromatase has been studied in search of potent and selective AIs as a substitute of the natural steroidal ligand. Structure‐based computational approach namely, molecular docking simulations were performed to investigate the structural features of the docked complex of aromatase and flavonoid ligands. A nonsteroidal flavonoid pharmacophore showing electrostatic and steric features for selective binding within the main pocket of the catalytic active site of aromatase has been identified as an outcome of the study. The binding affinity of quercetin and isoflavone were predicted within aromatase. Isoflavone was used as a negative control to compare its binding affinities with the selected dataset. The predicted binding affinity of negative control isoflavone was in accordance with its in vitro AI efficacy. Isoflavone showed poor binding affinity and ranked last in terms of MolDock score (−86.309 kcal/molÅ) compared to dataset molecules. The generated pharmacophoric information will be helpful for the synthetic chemist to design and synthesize selective AIs with comparable binding affinity to the natural steroidal ligand.

In silico docking and ADME study of deketene curcumin derivatives (DKC) as an aromatase inhibitor or antagonist to the estrogen-alpha positive receptor (Erα+): potent application of breast cancer

“…On the other hand, some natural products or phytochemicals have been docked for the same disease. For example, Rahman et al and Thareja et al used compounds such as abruquiones and flavonoids, which have MolDock scores of −86.309 and −94.36 kcal/mol, respectively [27,28]. Additionally, these studies' minimum binding affinity values are relatively low in comparison to ours.…”

Isolation, Characterization and in Silico Studies of Secondary Metabolites from Jurinea macrocephala DC. with Antiproliferative Activity

“…Therefore, the discovery of new aromatase inhibitors including plant‐based derivatives is of utmost importance. Among them, the aromatase inhibition potential of flavonoids has been widely discussed in the literature [26–30] . With this motivation, we decided to examine the interactions of 1 – 12 within the active site of aromatase as the potential target enzyme for the anticancer activity against MCF‐7 cell lines.…”