Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha.

Muchtaridi Muchtaridi,Sharon Bryant,Anas Subarnas,Thierry Langer,Hasna Syahidah,Muhammad Yusuf

doi:10.3390/ph10040081

Abstract

Tamoxifen is the most frequently used anti-estrogen adjuvant treatment for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of several serious side–effects, such as uterine cancer, stroke, and pulmonary embolism. The 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) from plant leaves of Eugenia aquea, has been found to inhibit the proliferation of MCF-7 human breast cancer cells in a dose-dependent manner, with an IC50 of 74.5 μg/mL (250 μM). The aim of this work was to study the molecular interactions of new ChalcEA derivatives formed with the Estrogen Receptor α (ERα) using computer aided drug design approaches. Molecular docking using Autodock 4.2 was employed to explore the modes of binding of ChalcEA derivatives with ERα. The 3D structure-based pharmacophore model was derived using LigandScout 4.1 Advanced to investigate the important chemical interactions of the ERα-tamoxifen complex structure. The binding energy and the tamoxifen-pharmacophore fit score of the best ChalcEA derivative (HNS10) were −12.33 kcal/mol and 67.07 kcal/mol, respectively. The HNS10 interacted with Leu346, Thr347, Leu349, Ala350, Glu353, Leu387, Met388, Leu391, Arg394, Met421, and Leu525. These results suggest that the new ChalcEA derivatives could serve as the lead compound for potent ERα inhibitor in the fight against breast cancer.

Highlights

Breast cancer accounts for more than 1.2 million new cases and 500,000 deaths annually
X-ray derived structure revealed that 4-OHT formed hydrophobic interactions predominantly with the butenyl group and aromatic rings, a positive ionizable interaction with primary the tertiary amine nitrogen and hydrogen bond interactions with the phenoxy and hydroxyl oxygens (Figure 1a,b)
Future studies will elaborate the synthesis and biological evaluation of the best predicted ChalcEA derivatives to assess their interaction with Estrogen Receptor α (ERα) and their potential for modulating anti-breast cancer activity

Summary

Introduction

Breast cancer accounts for more than 1.2 million new cases and 500,000 deaths annually. It is the leading cause of cancer death among females (23% of total cancer and 14% of cancer mortality cases) [1]. Mortality in women due to this cancer in both developed (189,000 deaths) and emerging (269,000 deaths) economies was reported to reach 15.5% and 12.7% of total breast cancer cases, respectively in 2012 [2]. ERα plays a role in cell proliferation and has been found in the endometrial, breast cancer and ovarian stromal cells, as well as in the hypothalamus [4]. The tamoxifen-bound ER complex inhibits the genes from being switched on by estrogen, leading to the prevention of the estrogenic effects responsible for cancer cell proliferation [6]

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