Docking Studies reveal Phytochemicals as the long searched Anticancer Drugs for Breast Cancer (original) (raw)
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Design, Synthesis, Anticancer Evaluation and Molecular Modeling of Novel Estrogen Derivatives
Molecules
A series of estrone derivatives 3–8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future.
Bangladesh Journal of Pharmacology, 2014
Breast cancer malignancy is prevailing among the women not only from the developing countries but also from the developed one at the rate of 18% of total population worldwide. One of the main causes of breast cancer is estrogen receptor alpha. Overexpression of estrogen receptor is seen in number of cases of breast cancer. Tamoxifen was used as a reference drug in present study. Almost 80,000 species of plants are used as a source of medicines. Current study was totally based on the screening of phytochemicals to find out the biomolecules having strong bonding actions as compared to tamoxifen. Present study exhibited that 10 molecules (kushenol K, silybin, taxifolin 3-O-acetate, rosemarinic acid, secundifloran, kushenol N, kurarinol, podophyllotoxone, AC1LCW2L, leachianone G) have successful and potential binding with the target molecule as compared to tamoxifen. These molecules can be used for the treatment of breast cancer and birth control.
Natural Compounds or Their Derivatives against Breast Cancer: A Computational Study
BioMed Research International
Background. Breast cancer is one of the most common types of cancer diagnosed and the second leading cause of death among women. Breast cancer susceptibility proteins of type 1 and 2 are human tumor suppressor genes. Genetic variations/mutations in these two genes lead to overexpression of human breast tumor suppressor genes (e.g., BRCA1, BRCA2), which triggers uncontrolled duplication of cells in humans. In addition, multidrug resistance protein 1 (MDR1), an important cell membrane protein that pumps many foreign substances from cells, is also responsible for developing resistance to cancer chemotherapy. Aim of the Study. The aim of this study was to analyze some natural compounds or their derivatives as part of the development of strong inhibitors for breast cancer. Methodology. Molecular docking studies were performed using compounds known in the literature to be effective against BRCA1 and BRCA2 and MDR1, with positive control being 5-fluorouracil, an antineoplastic drug as a po...
Journal of the Turkish Chemical Society, Section A: Chemistry, 2018
Molecular docking and pharmacokinetic study were performed on 20 selected phytochemicals with estrogen and progesterone receptors and it was found that all the phytochemicals has strong binding energy and high number of interactions when docked with estrogen and progesterone receptors, Gabridin has the highest binding energy of-10.3 kcal/mol and 12 numbers of various interactions when docked with estrogen receptor, while Quercetin has the highest binding energy of-9.6 kcal/mol and about 14 numbers of various interactions when docked with progesterone receptor. Pharmacokinetic study carried out revealed that all the leading compounds (Gabridin and Quercetin) are in agreement with Lipinski rule of five without violating any of the conditions of bioavailability, this has shown that they will be readily bioavailable. With the high binding affinity of these compounds and good pharmacokinetic parameters, most of the phytochemicals used in this study can be used in designing a highly effective and readily bioavailable anti breast cancer drug.
Oxidative Medicine and Cellular Longevity
Breast cancer (BC) is the leading cause of death among women worldwide devoid of effective treatment. It is therefore important to develop agents that can reverse, reduce, or slow the growth of BC. The use of natural products as chemopreventive agents provides enormous advantages. The aim of the current investigation is to determine the efficacy of the phytochemicals against BC along with the approved drugs to screen the most desirable and effective phytocompound. In the current study, 36 phytochemicals have been evaluated against aromatase to identify the potential candidate drug along with the approved drugs employing the Cdocker module accessible on the Discovery Studio (DS) v4.5 and thereafter analysing the stability of the protein ligand complex using GROningen MAchine for Chemical Simulations v5.0.6 (GROMACS). Additionally, these compounds were assessed for the inhibitory features employing the structure-based pharmacophore (SBP). The Cdocker protocol available with the DS has...
Indian Journal of Biotechnology
Breast cancer is a prominent disorder that affects mostly mid aged women with a high intensity, upsetting every ninth women of ten. The available drugs and treatments fall back as they do not completely eradicate the cancerous cells from body. Hence, newer and more effective drugs and treatments against breast cancer are the need-of-hour. The increased level of estrogen within body increases the chance of breast cancer, whereas the regular concentration plays significant role in normal cell functioning. Melatonin is popularly used as an anti-estrogenic compound, whereas violacein an active secondary metabolite secreted by bacteria like 'Chromobacterium violaceum' has strong structural similarity with melatonin and, thus, possess latency of being tested for its anti-cancerous activity. In the current study, docking and virtual screening was utilized to prove the fact that violacein and similar compounds can bind more efficiently to estrogen receptor than that of melatonin and...
Phytochemicals based therapeutic approaches for Breast cancer targeting: Molecular docking study
Background: Cancer is a prominent cause of disease burden all over the world. Primary cause of the development of cancer is exposure to potentially hazardous environmental factors and unhealthy lifestyle. Among all types of cancer, breast cancer is most common in women and becomes a public health issue on a global scale. There has been considerable interest in the development of drugs which can target cancer-causing hotspot factors such as mTOR, estrogen receptor alpha, and progesterone receptor to cure breast cancer. The key focus of the present work is to search plant-based phytochemical molecules which can efficiently interact with the targeted proteins responsible for the development and progression of breast cancer using molecular docking studies. Methods: We have screened 1064 phytochemical molecules from plant sources against 5 potential hotspot targets: EGFR kinase domain, Human estrogen receptor alpha ligand-binding domain, FRB fragment of mTOR, Progesterone receptor, and N...
Journal of Pharmaceutical Research International
Aromatase plays a significant role in the progression of estrogen receptor-positive (ER-positive) breast cancer. The adverse side effects of currently used aromatase inhibitors (AIs) necessitate the development of new AIs that are more active, selective, and less toxic. This study used a computational approach to screen 503 natural compounds ZINC database against the aromatase active site. The best scoring hits ZINC69482055, ZINC69482510, and ZINC406719 exhibited strong binding with aromatase, with binding energy values of -8.45, -10.35, and -8.75 kcal/mol, respectively, which is comparatively higher than that of the control compound Anastrozole (-6.43 kcal/mol). Docking analysis showed that the selected hits interacted with the crucial residues of the aromatase active site. This study suggested that these compounds could be used as possible AIs in the cure of breast cancer. Hands-on bench work validation is needed to optimize these compounds as AIs.
Journal of Molecular Modeling, 2018
Nowadays, breast cancer is one of the most widespread malignancies in women, and the second leading cause of cancer death among women. The progesterone receptor (PR) is one of the treatment targets in breast cancer, and can be blocked with selective progesterone receptor modulators (SPRMs). Since administration of chemical drugs can cause serious side effects, and patients, especially those undergoing long-term treatment, can suffer harmful consequences, there is an urgent need to discover novel potent drugs. Large-scale structural diversity is a feature of natural compounds. Accordingly, in the present study, we selected a library of 20,000 natural compounds from the ZINC database, and screened them against the PR for binding affinity and efficacy. In addition, we evaluated the pharmacodynamics and ADMET properties of the compounds and performed molecular docking. Moreover, molecular dynamics (MD) simulation was carried out in order to examine the stability of the protein. In addition, principal component analysis (PCA) was performed to study the motions of the protein. Finally, the MMPBSA method was applied in order to estimate the binding free energy. Our docking results reveal that compounds ZINC00936598, ZINC00869973 and ZINC01020370 have the highest binding energy into the PR binding site, comparable with that of Levonorgestrel (positive control). Moreover, RMSD, RMSF, Rg and H-bond analysis demonstrate that the lead compounds preserve stability in complex with PR during simulation. Our PCA analysis results were in accordance with MD results and the binding free energies support the docking results. This study paves the way for discovery of novel drugs from natural sources and with optimal efficacy, targeting the PR.
In Silico Pharmacology, 2020
Breast cancer is one of the leading causes of death among women. We employed in silico model to predict the mechanism of actions of selected novel compounds reported against breast cancer using ADMET profiling, drug likeness and molecular docking analyses. The selected compounds were andrographolide (AGP), dipalmitoylphosphatidic acid (DPA), 3-(4-Bromo phenylazo)-2,4-pentanedione (BPP), atorvastatin (ATS), benzylserine (BZS) and 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD). These compounds largely conform to ADMETlab and Lipinki's rule of drug likeness criteria in addition to their lesser hepatotoxic and mutagenic effects. Docking studies revealed a strong affinity of AGP versus NF-kB (− 6.8 kcal/ mol), DPA versus Cutlike-homeobox (− 5.1 kcal/mol), BPP versus Hypoxia inducing factor 1 (− 7.7 kcal/mol), ATS versus Sterol Regulatory Element Binding Protein 2 (− 7.2 kcal/mol), BZS versus Ephrin type-A receptor 2 (− 4.4 kcal/mol) and TCD versus Ying Yang 1 (− 9.4 kcal/mol). Likewise, interaction between the said compounds and respective gene products were evidently observed with strong affinities; AGP versus COX-2 (− 9.6 kcal/mol), DPA versus Fibroblast growth factor receptor (− 5.9 kcal/mol), BPP versus Vascular endothelial growth factor (− 5.8 kcal/mol), ATS versus HMG-COA reductase (− 9.1 kcal/mol), BZS versus L-type amino acid transporter 1 (− 5.3 kcal/mol) and TCD versus Histone deacytylase (− 7.7 kcal/mol), respectively. The compounds might potentially target transcription through inhibition of promoter-transcription factor binding and/or inactivation of final gene product. Thus, findings from this study provide a possible mechanism of action of these xenobiotics to guide in vitro and in vivo studies in breast cancer.