Pharmacophore Modeling and Molecular Docking of Flavonoid Derivatives in Abelmoschus manihot Against Human Estrogen Receptor Alpha of Breast Cancer

Abstract

Tamoxifen is the most commonly used anti-estrogen adjuvant therapy for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of some serious side effects, such as uterine cancer, stroke, and pulmonary embolism. The flavonoid compounds in the leaves of A. manihot inhibited the growth of 4T1 breast cancer cells at a CTC50 concentration of 185.06 μg/ml. Therefore, this study aims to examine the molecular interactions and pharmacophore modeling based on the interaction of 4-OHT with human ER, followed by the molecular docking of the flavonoid derivatives with human ERα. The molecular docking simulations and 3D structure-based pharmacophore models were used to identify the molecular interactions of flavonoid derivatives in A. manihot on estrogen receptors (ERα) (PDB ID: 3ERT). The results showed that the binding energies of the flavonoid derivatives in isorhamnetin and isoquercitrin were -8.68 kcal/mol and -8.75 kcal/mol, respectively. This compound also interacted with Arg394 and Glu353 important amino acid residues in the ERα-binding pocket. Meanwhile, the pharmacophore fit scores of isorhamnetin and isoquercitrin were 82.36% and 84.91%, respectively. The flavonoid derivatives in A. manihot had pharmacophore fit resulting from the 4-OHT complex with ER, and therefore they had potential as ERα antagonists. Out of the 10 flavonoid derivatives, isorhamnetin and isoquercitrin showed the best docking scores and could be used as candidates for new anti-breast cancer drugs with antagonistic activity against ERα.