Repurposing of Benzimidazole Scaffolds for HER-2 Positive Breast Cancer Therapy: An In-Silico Approach

2020 ◽  
Vol 12 ◽  
Author(s):  
Selvaraj Jubie ◽  
Uma Durai ◽  
Subbiah Latha ◽  
Selvaraj Ayyamperumal ◽  
Ashish Wadhwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
In Silico ◽  
Safety Data ◽  
Cancer Drug ◽  
Anticancer Activities ◽  
Binding Studies ◽  
Discovery Studio ◽  
Cytotoxicity Activity ◽  
Her 2

Background: A newer trend has been hoisted recently to reuse of the conventional drugs with distinct indications for the newer applications to speed up the drug discovery and development based on earlier acquaintance and safety data. Most of the non-cancerous agents could afford a little or tolerable side effects in individual. However, repositioning of these non-cancerous agents for successful anticancer therapy is an outstanding strategy for future anti-cancer drug development. Since more diverse and selective cancer drug targets are being discovered and developed, the approved drug collections are particularly useful to quickly identify clinically advanced anticancer drugs against those targets. Objective: Antihelminthic drugs such as Mebendazole and Albendazole (Benzimidazole class) have been reported to exhibited cytotoxicity (or anticancer activities) against several types of cancer. Therefore, this study aims to repurpose the benzimidazole scaffold for breast cancer treatment. Method: In the present study, three hydrazone analogs having benzimidazole motif in their structural frame were synthesized. Their in-silico binding studies against HER-2 receptor (PDB ID: 4LQM) and ADMET studies were carried out using Accelrys drug discovery studio 4.1. Cytotoxicity of the synthesized compounds against HER-2 overexpressed MCF-7 cell lines was determined by MTT assay. Result: One of the compound 2-[2-(2,4-dinitrophenyl)hydrazinylidene]-2,3-dihydro-1H-benzimidazole (U1) has shown good cytotoxicity activity when compared to the standard lapatinib which is a well known HER-2 inhibitor. Conclusions: Thus, the designed benzimidazole scaffold might serve as the best leads for treating the breast cancer, which is additionally confirmed by performing their docking study via Accelrys discovery studio.

scholarly journals PheWAS-Based Systems Genetics Methods for Anti-Breast Cancer Drug Discovery

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 154
Author(s):  
Min Gao ◽  
Yuan Quan ◽  
Xiong-Hui Zhou ◽  
Hong-Yu Zhang
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Association Studies ◽  
Biological Significance ◽  
Cancer Drug ◽  
Systems Genetics ◽  
Cancer Genes ◽  
Genome Wide ◽  
A Genome ◽  
Breast Cancer Genes

Breast cancer is a high-risk disease worldwide. For such complex diseases that are induced by multiple pathogenic genes, determining how to establish an effective drug discovery strategy is a challenge. In recent years, a large amount of genetic data has accumulated, particularly in the genome-wide identification of disorder genes. However, understanding how to use these data efficiently for pathogenesis elucidation and drug discovery is still a problem because the gene–disease links that are identified by high-throughput techniques such as phenome-wide association studies (PheWASs) are usually too weak to have biological significance. Systems genetics is a thriving area of study that aims to understand genetic interactions on a genome-wide scale. In this study, we aimed to establish two effective strategies for identifying breast cancer genes based on the systems genetics algorithm. As a result, we found that the GeneRank-based strategy, which combines the prognostic phenotype-based gene-dependent network with the phenotypic-related PheWAS data, can promote the identification of breast cancer genes and the discovery of anti-breast cancer drugs.

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

2018 ◽  
Vol 15 (1) ◽  
pp. 89-96 ◽  
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 (ER&#945;) correlates with better prognosis and the likelihood of response to hormonal therapy. ER&#945; 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 &#177; 4.0 and 58.3 &#177; 4.4 &#181;M, 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.

Spectroscopic and In Silico DNA Binding Studies on the Interaction of Some New N-Substituted Rhodanines with Calf-thymus DNA: In Vitro Anticancer Activities

2019 ◽  
Vol 19 (3) ◽  
pp. 425-433 ◽  
Author(s):  
Imran Ali ◽  
Mohammad N. Lone ◽  
Zeid A. Alothman ◽  
Ahmad Y. Badjah ◽  
Abdullah G. Alanazi
Keyword(s):  
Dna Binding ◽  
Anticancer Agents ◽  
In Silico ◽  
Calf Thymus Dna ◽  
Black Dot ◽  
Anticancer Activities ◽  
Binding Studies ◽  
Molecular Docking Study ◽  
Calf Thymus ◽  
Dna Binding Studies

Background: In this era of science, cancer is a black dot on the face of humankind. Consequently, the search of promising anticancer agents continues. Aims: Here we designed and synthesized new N-substituted rhodanines (RD1-7), evaluated their multispectroscopic interaction with calf thymus DNA, in silico and anticancer studies against MDA-MB-231cancer cell line. Methods: By MTT assay rhodanine RD1 was found to be the most potent with IC50 value of 72.61 μM. In addition, DNA binding studies (UV-vis and fluorescence) revealed strong binding affinity of RD1-7 with DNA (Kb in the range of 1.5-7.4 × 105 M-1). Moreover, molecular docking study, experimental DNA binding and anticancer studies are all well agreed to each other. Results: It was observed that H-bonding and hydrophobic attractions were responsible for stability of DNAcompound adducts. Besides, the reported rhodanines (RD1-7) were found as minor groove binders of DNA. Concisely, RD1-7 indicated promising pharmacological properties and hence, shows auspicious future for the development of novel anticancer agents. Conclusion: The reported rhodanines showed excellent anticancer properties. Therefore, the described rhodanines may be used as potential anticancer agents in the future.

Design, Synthesis, Anti-Proliferative, Anti-microbial, Anti-Angiogenic Activity and In Silico Analysis of Novel Hydrazone Derivatives

2019 ◽  
Vol 19 (13) ◽  
pp. 1658-1669 ◽  
Author(s):  
Hakan Ünver ◽  
Burak Berber ◽  
Rasime Demirel ◽  
Ayşe T. Koparal
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
In Silico ◽  
Proliferative Activity ◽  
Research Work ◽  
Target Prediction ◽  
Cancer Drug ◽  
Breast Cancer Cell Lines ◽  
Tertiary Butyl ◽  
Prediction Analysis

Background: Cancer is the second leading cause of death globally. Hydrazone and hydrazone derivatives have high activity, and for this reason, these compound are greatly used by researchers to synthesize new anti-cancer drug. The aim of this research work is to synthesize novel anticancer agents. Methods: New hydrazone derivatives were synthesized via a reaction between 3-formylphenyl methyl carbonate and benzhydrazide, 4-methylbenzoic hydrazide, 4-tert-butylbenzoic hydrazide, 4-nitrobenzoic hydrazide and 3- methoxybenzoic hydrazide, and were successfully characterized using elemental analysis, 1H-NMR, 13C-NMR, FT-IR and LC-MS techniques. The synthesized compounds were evaluated for their antimicrobial (some grampositive and -negative bacteria, filamentous fungi and yeasts), anti-proliferative (T47D and HCC1428-breast cancer cells) and anti-angiogenic (HUVEC-endothelial cells) activities. The anti-proliferative activities of the hydrazone compounds R1-R5 were studied on these cell lines by MTT assay. The anti-angiogenic potential of the compounds was determined by the endothelial tube formation assay. To identify structural features related to the anti-proliferative activity of these compounds, 2D-QSAR was performed. Results: The results indicated that compound R3 exhibited strong anti-angiogenic and anti-proliferative activity on breast cancer cell lines and healthy cell lines. Also, this compound; possessing a tertiary butyl moiety on the hydrazine, exhibited the highest inhibitory effect against all tested microorganisms; in particular, it inhibited Candida albicans at a lower concentration than ketoconazole. Among the investigated compounds, those bearing methyl, tertiary butyl (compound R2, R3) and methoxy (compound R5) moiety were found to be more successful anticandidal derivatives than standard antifungal antibiotics. The QSAR analysis suggested that the tumor specificity of the hydrazone correlated with their molecular weight, lipophilicity, molar refractivity, water solubility, DipolHybrid:(MOPAC) and ExchangeEnergy:(MOPAC). Absorption, Distribution, Metabolism and Elimination (ADME) analysis of the hydrazone compounds showed that they have favorable pharmacokinetic and drug-likeness properties. The ADME results clarify that R3 is the best compound in terms of pharmacokinetic properties. In contrast to other compounds; target prediction analysis of the compound R3 showed inhibitory activity on estrogen-related receptor alpha transcription factor (ESRRA). The target prediction analysis was supported by molinspiration bioactivity score. Conclusion: The R3 compound is considered to be an important candidate for future studies with its suitability for the Lipinski’s rule of five for drug-likeness, and effective in vitro and in silico results.

In Silico Studies of Green Tea Catechins Against HER-2 Receptor in Breast Cancer

2020 ◽  
Vol 14 (5) ◽  
pp. 194-199
Author(s):  
Fitriyani Fitriyani F ◽  
Taufik M Fakih ◽  
Daryono H Tjahjono
Keyword(s):  
Breast Cancer ◽  
Green Tea ◽  
In Silico ◽  
Tea Catechins ◽  
Green Tea Catechins ◽  
In Silico Studies ◽  
Her 2

Abstract 2675: Characterization of human thioesterase 2 and its potential for breast cancer drug discovery

2010 ◽  
Author(s):  
Melissa K. Ritchie ◽  
Lynnette C. Johnson ◽  
Laura A. Watts ◽  
Steven J. Kridel ◽  
W. Todd Lowther
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Cancer Drug ◽  
Cancer Drug Discovery

scholarly journals ANTI CANCER STUDIES OF SELECTIVE MANNICH BASES BY IN SILICO METHOD

2018 ◽  
Vol 10 (2) ◽  
pp. 81 ◽  
Author(s):  
L. Muruganandam ◽  
Maheswari R.
Keyword(s):  
Estrogen Receptor ◽  
In Silico ◽  
Mannich Bases ◽  
Receptor Protein ◽  
Crystallographic Structure ◽  
Anticancer Activities ◽  
Standard Drug ◽  
Estrogen Receptor Protein ◽  
Discovery Studio

Objective: To evaluate the anticancer activities of selective Mannich bases by in silico methods.Methods: X-ray crystallographic structure of Estrogen receptor protein (PDB ID 2YAT) was downloaded from the protein data bank (PDB) and is docked with the target Mannich bases using Accelyrs Discovery Studio client version 2.5 software.Results: Based on the in silico analysis results of the target compounds with standard drug tamoxifen, the best-docked compound is identified and its anticancer activity is confirmed by using in vitro MTS analysis using Raju and Jurkat cell lines.Conclusion: The mannich base compound N-[(Diphenylamino) methyl] acetamide showed fourfold higher activity than standard drug tamoxifen, may be used to overcome the drug resistance of Estrogen receptor protein.

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