Cytotoxicity of chalcone of eugenia aquea burm F. leaves against T47D breast cancer cell lines and its prediction as an estrogen receptor antagonist based on pharmacophore-molecular dynamics simulation

Abstract

Background: The 2',4'-dihydroxy-6-methoxy-3,5-3-dimethylchalcone (ChalcEA) isolated from Eugenia aquea Burm f. leaves has potential anticancer activity against human breastadenocarcinoma cell lines (MCF-7) with an IC50 value of 250µM. However, its apoptotic activity on the T47D breast cancer cell lines which is involving caspase-3 has not been investigated. Materials and methods: Therefore, this study aims to evaluate the cytotoxicity of ChalcEA on the T47D cell lines using the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)- 2H-tetrazolium (WST) method and to predict its possible antagonistic activity on the human estrogen receptor alpha (hERa) using pharmacophore and molecular dynamics (MD) methods. The in vitro test of 10 synthesized ChalcEA derivatives was also performed as an insight into the further development of its structure as an anticancer agent. Results: It is shown that ChalcEA has an IC50 of 142.58 ± 4.6 µM against the hERa-overexpressed T47D breast cancer cell lines, indicating its possible mechanism of anticancer activity as an antagonist of hERa. Pharmacophore study showed that ChalcEA shares similar features with the known hERa antagonist, 4-hydroxytamoxifen (4-OHT), which has hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), ring aromaticity (RA), and hydrophobicity (Hy) features. Molecular docking showed that ChalcEA formed hydrogen bonds with Glu353 and Arg394, and hydrophobic interactions in a similar manner with 4-OHT. Moreover, MD simulations showed that ChalcEA destabilized the conformation of His524, a remarkable behavior of a known hERa antagonist, including 4-OHT. Furthermore, the 10 best chalcone derivatives resulted from pharmacophore- and docking-based screening, were tested against the T47D cell lines. None of the derivatives have better activity than ChalcEA. It is suggested that the functional groups at the B-ring of ChalcEA are interesting to be further optimized in the next studies. Conclusion: ChalcEA might act as an antagonist toward hERa, thus warranting further investigation as a potential anticancer agent.