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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

Authors Muchtaridi M, Yusuf M, Syahidah HN, Subarnas A, Zamri A, Bryant SD, Langer T

Received 26 May 2019

Accepted for publication 22 October 2019

Published 6 November 2019 Volume 2019:12 Pages 33—43


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Juan Fernandez-Recio

Muchtaridi Muchtaridi,1 Muhammad Yusuf,2 Hasna Nur Syahidah,1 Anas Subarnas,1 Adel Zamri,3 Sharon D Bryant,4 Thierry Langer5

1Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, West Java, Indonesia; 2Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Bandung, West Java, Indonesia; 3Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Riau, Pekanbaru, Riau 26293, Indonesia; 4Inte:Ligand GmbH, Mariahilferstrasse, Vienna 1070, Austria; 5Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna A-1090, Austria

Correspondence: Muchtaridi Muchtaridi Tel/fax +62-22-7796200

Background: The 2ʹ,4ʹ-dihydroxy-6-methoxy-3,5-3-dimethylchalcone (ChalcEA) isolated from Eugenia aquea Burm f. leaves has potential anticancer activity against human breast-adenocarcinoma cell lines (MCF-7) with an IC50 value of 250 μM. 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 (hERα) 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 hERα-overexpressed T47D breast cancer cell lines, indicating its possible mechanism of anticancer activity as an antagonist of hERα. Pharmacophore study showed that ChalcEA shares similar features with the known hERα 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 hERα, thus warranting further investigation as a potential anticancer agent.

Keywords: chalcone, estrogen receptor, pharmacophore, molecular docking, molecular dynamics

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