In silico selection of an aptamer to estrogen receptor alpha using computational docking employing estrogen response elements as aptamer-alike molecules

A cyclooxygenase-2 (COX-2) inhibitor celecoxib has been previously reported to have cytotoxic activities towards gastric, prostate, ovarian, colon and breast cancer cell lines. This article reports that the cytotoxic activities of celecoxib could be resulted from its activity as a potent ligand for estrogen receptor alpha (ERα). Aided by molecular docking simulations, an in silico test to examine whether celecoxib is a ligand for estrogen receptor alpha (ERα) was performed followed by in vitro test employing cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. The compound was extracted from Celebrex®. Measured by using UV spectrophotometric method at 255.5 nm, it was identified that the content of celecoxib was 102.15 mg/271.48 mg capsule content. The in silico test indicated that celecoxib is a potent ligand for ERα. This finding was confirmed experimentally by an in vitro test that celecoxib has a comparable activity as an ERα ligand to tamoxifen, a drug of choice for breast cancer treatment.

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In silico Molecular Modelling of Selected Natural Ligands and their Binding Features with Estrogen Receptor Alpha

Current Computer - Aided Drug Design ◽

10.2174/1573409914666181008165356 ◽

2018 ◽

Vol 15 (1) ◽

pp. 89-96 ◽

Cited By ~ 5

Author(s):

V.L. Maruthanila ◽

R. Elancheran ◽

Nand Kishor Roy ◽

Anupam Bhattacharya ◽

Ajaikumar B. Kunnumakkara ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Line ◽

In Silico ◽

Estrogen Receptor Alpha ◽

Natural Compounds ◽

Pharmacokinetic Parameters ◽

Anticancer Activities ◽

Receptor Alpha ◽

Mcf 7

Background: Breast cancer is one of the most common cancers diagnosed among women. It is now recognized that two receptors mediate estrogen action and the presence of estrogen receptor alpha (ERα) correlates with better prognosis and the likelihood of response to hormonal therapy. ERα is an attractive target for the treatment of breast cancer. Most of the drugs currently used for the breast cancer treatment have numerous side effects and they are often unsuccessful in removing the tumour completely. Hence, we focused on natural compounds like flavonoids, polyphenols, etc. which do not exhibit any high toxic effects against normal cells. </P><P> Objectives: To identify the potential natural inhibitors for BCa through an optimised in silico approach. </P><P> Methods: Structural modification and molecular docking-based screening approaches were imposed to identify the novel natural compounds by using Schrödinger (Maestro 9.5). The Qikprop v3.5 was used for the evaluation of important ADME parameters and its permissible ranges. Cytotoxicity of the compounds was evaluated by MTT assay against MCF-7 Cell lines. Results: From the docking studies, we found that the compounds, Myricetin, Quercetin, Apigenin, Luteolin and Baicalein showed the highest Glide Scores -10.78, -9.48, -8.92, -8.87 and -8.82 kcal mol-1 respectively. Of these, Luteolin and Baicalein showed the significant IC50 values (25 ± 4.0 and 58.3 ± 4.4 µM, respectively) against MCF-7 cell line. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. We mainly focused on in silico study to dock the compounds into the human estrogen receptor ligand binding domain (hERLBD) and compare their predicted binding affinity with known antiestrogens. Myricetin, Quercetin, Apigenin, Luteolin and Baicalein were identified as the most promising among all. Of these, Luteolin and Baicalein showed significant anticancer activities against MCF-7 cell line. These findings may provide basic information for the development of anti-breast cancer agents.

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