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In today's world the pursuit of novel anti cancer agent remains top priority because of the fact that global burden of this malady is continuously increasing. Our work is no different from others in searching for new therapeutic solutions. To achieve this we are looking into Epigenetics, the phenomenon governed by hypermethylation and hypomethylati...
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... these, the later five fall under Lipinski's rule of five (RO5). Table 1 shows the above described data of the top six compounds. The above-mentioned properties play a pivotal role in deciding the fate of the compound and analyzing them in silico not only saves time but also is economically less challenging. ...
Citations
... However, the functions and mechanisms of action of cuproptosis-related genes in HNSCC warrant further investigation. Molecular dynamics simulation serves as one of the important tools for assessing the stability of drug-targeting ligands for the development of oncological therapeutics (Chikan and Vipperla, 2015;Thai et al., 2015). The aim of this study was to identify cuproptosis-related genes associated with poor prognosis of HNSCC and screen for potential candidate drugs for its treatment using molecular docking and molecular dynamics simulations. ...
Head and neck squamous cell carcinoma (HNSCC), the most common malignancy of the head and neck, has an overall 5-year survival rate of <50%. Genes associated with cuproptosis, a newly identified copper-dependent form of cell death, are aberrantly expressed in various tumours. However, their role in HNSCC remains unknown. In this study, bioinformatic analysis revealed that the cuproptosis-related gene CDKN2A was correlated with the malignant behaviour of HNSCC. Kaplan-Meier (KM) curves showed that patients with high CDKN2A expression had a better prognosis. Multiomic analysis revealed that CDKN2A may be associated with cell cycle and immune cell infiltration in the tumour microenvironment and is important for maintaining systemic homeostasis in the body. Furthermore, molecular docking and molecular dynamics simulations suggested strong binding between plicamycin and CDKN2A. And plicamycin inhibits the progression of HNSCC in cellular assays. In conclusion, this study elucidated a potential mechanism of action of the cuproptosis-associated gene CDKN2A in HNSCC and revealed that plicamycin targets CDKN2A to improve the prognosis of patients.
... Through computer-aided drug designing methods, it has been shown that a natural compound (chem. ID 28127) can strongly inhibit Kaiso (183). However, detailed experimental evidence is needed in this regard. ...
DNA methylation is a major epigenetic process that regulates chromatin structure which causes transcriptional activation or repression of genes in a context-dependent manner. In general, DNA methylation takes place when methyl groups are added to the appropriate bases on the genome by the action of “writer” molecules known as DNA methyltransferases. How these methylation marks are read and interpreted into different functionalities represents one of the main mechanisms through which the genes are switched “ON” or “OFF” and typically involves different types of “reader” proteins that can recognize and bind to the methylated regions. A tightly balanced regulation exists between the “writers” and “readers” in order to mediate normal cellular functions. However, alterations in normal methylation pattern is a typical hallmark of cancer which alters the way methylation marks are written, read and interpreted in different disease states. This unique characteristic of DNA methylation “readers” has identified them as attractive therapeutic targets. In this review, we describe the current state of knowledge on the different classes of DNA methylation “readers” identified thus far along with their normal biological functions, describe how they are dysregulated in cancer, and discuss the various anti-cancer therapies that are currently being developed and evaluated for targeting these proteins.
... At the very least, identification and exploration of the targets of such epigenetic transcriptional regulators which may influence cell polarity could prove to be of value to the field of cancer research. As Kaiso inhibition has been suggested as a potential therapeutic strategy for the treatment of colorectal cancer, and inhibitors for this transcriptional repressor are currently being investigated (50). The work presented here indicates that the tumor-suppressive effect of Kaiso loss is limited to systems in which functional Dlg1 is present at the initiation stage of a tumor. ...
Both alterations to the epigenome and loss of polarity have been linked to cancer initiation, progression, and metastasis. It has previously been demonstrated that loss of the epigenetic reader protein Kaiso suppresses intestinal tumorigenesis in the Apc+/min mouse model, in which altered polarity plays a key role. Thus, we investigated the link between Kaiso deficiency, polarity, and suppression of intestinal tumorigenesis. We used Kaiso-deficient mice to conditionally delete Apc within the intestinal epithelia and demonstrated upregulation of the spindle polarity genes Dlg1 and Dlgap1. To understand the role of Dlg1, we generated Villin-creApc+/minDlg1flx/flx Kaiso−/y mice to analyze gene expression, survival, tumor burden, and spindle orientation. In vivo analysis of the Dlg1-deficient intestine revealed improper orientation of mitotic spindles and a decreased rate of cellular migration. Loss of Dlg1 decreased survival in Apc+/min mice, validating its role as a tumor suppressor in the intestine. Significantly, the increased survival of Apc+/minKaisoy/− mice was shown to be dependent on Dlg1 expression. Taken together, these data indicate that maintenance of spindle polarity in the intestinal crypt requires appropriate regulation of Dlg1 expression. As Dlg1 loss leads to incorrect spindle orientation and a delay in cells transiting the intestinal crypt. We propose that the delayed exit from the crypt increase the window in which spontaneous mutations can become fixed, producing a “tumor-permissive” environment, without an increase in mutation rate.
Implications
Loss of mitotic spindle polarity delays the exit of cells from the intestinal crypt and promotes a tumorigenic environment.
... However, Kaiso deficiency does not result in neurodegeneration, reduction of learning ability or memory. Moreover, Zbtb33 gene knockout produces a visible antitumor effect [34] and Kaiso inhibitors are suggested to be potential antitumor agents [34,66]. Here we hypothesize that Kaiso inhibitors may possess possible antidepressant and antipsychotic activities in addition to their antitumor activity. ...
Kaiso is a bimodal transcriptional repressor. It binds methylated CpG islands or the sequence-specific consensus in the DNA molecule with the Kaiso zinc-finger domain and recruits repressive protein complexes to these DNA fragments by the interaction of the BTB/POZ domain with the complex of NCoR1 corepressor and histone deacetylase, thereby performing transcription repression. Kaiso is involved in epigenetic regulation of transcription. Moreover, the complex Kaiso and catenin p120ctn modulates the transcription of the Wnt-target genes. The review discusses the role of Kaiso in the central nervous system. Kaiso molecules are abundant in the brain. MRI study did not show any alterations in the whole brain, hippocampus and striatum in Kaiso null mice. However, in Kaiso deficient mice the lateral ventricles were three-fold smaller compared with wild-type control. Kaiso deficiency increased the locomotor and exploratory activities as well as the prepuls inhibition of acoustic startle reflex without any adverse effect on anxiety-related behavior, learning and memory. At the same time, Kaiso deficiency produces a marked antidepressant-like effect. Thus, Kaiso involved in the mechanism of locomotion and depressive-like behavior. Kaiso inhibitors are expected to be promising atypical antidepressant drugs.
... The results showed that the first 6 eigenvectors formed 90% of the total motion of the complex. The first 2 components of the eigenvectors were projected at 300 K and analysis of this revealed the clusters of stable states for the complex (41). The FEL was plotted over this projection, which provided a clear description of the stability of the complex (Fig. 8). ...
The control and treatment of rheumatoid arthritis is a challenge in today's world. Therefore, the pursuit of natural disease-modifying antirheumatic drugs (DMRDs) remains a top priority in rheumatology. The present study focused on curcumin and its derivatives in the search for new DMRDs. We focused on prominent p38 mitogen-activated protein (MAP) kinase p38α which is a prime regulator of tumor necrosis factor-α (TNF-α), a key mediator of rheumatoid arthritis. In the present study, we used the X-ray crystallographic structure of p38α for molecular docking simulations and molecular dynamic simulations to study the binding modes of curcumin and its derivatives with the active site of p38α. The ATP-binding domain was used for evaluating curcumin and its derivatives. Molecular docking simulation results were used to select 4 out of 8 compounds. These 4 compounds were simulated using GROMACS molecular simulation platform; the results generated were subjected to molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) calculations. The results showed cyclocurcumin as a potential natural compound for development of a potent DMRD. These data were further supported by inhibition of TNF-α release from lipopolysaccharide (LPS)-stimulated human macrophages following cyclocurcumin treatment.
... Epi-drugs of nucleoside origin are in use for treatment; however, non-nucleoside epi-drugs are in developmental stage. In silico studies have been used for epi-drug discovery [11][12][13]; in the present study, we used a similar approach to examine the possible binding mode of reported non-nucleoside DNMT1 inhibitors using AutoDock. ...
Purpose: To explore in silico methods to search for the best reported non-nucleoside DNA methyltransferase 1 (DNMT1) inhibitor of epimutation in gastric cancer. Methods: A dataset of reported non-nucleoside DNMT1 inhibitors was used to target the active site of crystallized DNMT1 protein. Molecular docking simulations were carried out using AutoDock 4.2.6 l. The results were analyzed using Discovery studio visualizer. Results: In silico analysis of known natural non-nucleoside DNMT1 inhibitors gave genistein as the top ranked compound with ΔG of -6.39 Kcal/mol. Further, the results indicated that epigallocatechin gallate and curcumin are poor non-nucleoside DNMT1 inhibitors, as the in silico data suggest that they failed to bind to the catalytic site of DNMT1. Conclusion: The results indicate that genistein is the top rated compound for DNMT1 inhibition. Previous in vitro and in vivo work by other researchers seem to validate the findings of the study. © Pharmacotherapy Group, Faculty of Pharmacy, 2017. All rights reserved.
... In silico approaches are a tool for drug discovery (23), which may be utilized for lead identification from large pools of drugs for further in vitro analysis. Molecular dynamics simulation is a tool that can be used to assess the stability of drug-target complexes (24). The present study used a computer-aided drug design (CADD) approach to identify compounds from an in-house pool of Chinese medicinal compounds for targeting EGFR for NSCLC treatment. ...
In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy. The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC). After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation. Triptolide, a top compound identified by this vigorous in silico screening, was then tested in vitro on the H2347 cell line carrying wild-type EGFR, revealing an anti-proliferative potency similar to that of known drugs against NSCLC.
DNA methylation is involved in numerous biological processes and is deregulated in human diseases. The modulation of the activity of the enzymes and proteins in charge of DNA methylation, for example, DNA methyltransferases (DNMTs), can represent a powerful strategy to alter DNA methylation patterns and restore biological processes that are aberrant in diseases. In this chapter, we present examples of inhibitors of DNMTs (DNMTi). We review their fields of application either as therapeutic molecules, for example, in cancers, cardiovascular, neurological, and infectious diseases or as bioengineering tools. Finally, novel strategies to target DNA methylation and overcome the limits of single DNMT inhibitors will be described. These strategies consist in either targeting the methyl group reader proteins rather than targeting directly DNMTs or to combine within the same molecule a DNMT inhibitor with an additional active moiety, e.g., HDAC inhibitor, to improve efficacy and lower secondary effect of such drug.KeywordsDNA methyltransferasesADNMT inhibitorsMethylbinding proteinsMBDtherapeutic strategieschemical biology
Background: Traditional Chinese Medicine (TCM) is widely utilized as complementary health care in China whose acceptance is still hindered by conventional scientific research methodology, although it has been exercised and implemented for nearly 2000 years. Identifying the molecular mechanisms, targets and bioactive components in TCM is a critical step in the modernization of TCM because of the complexity and uniqueness of the TCM system. With recent advances in computational approaches and high throughput technologies, it has become possible to understand the potential TCM mechanisms at the molecular and systematic level, to evaluate the effectiveness and toxicity of TCM treatments. Bioinformatics is gaining considerable attention to unearth the in-depth molecular mechanisms of TCM, which emerges as an interdisciplinary approach owing to the explosive omics data and development of computer science. Systems biology, based on the omics techniques, opens up a new perspective which enables us to investigate the holistic modulation effect on the body.
Objective: This review aims to sum up the recent efforts of bioinformatics and omics techniques in the research of TCM including Systems biology, Metabolomics, Proteomics, Genomics and Transcriptomics.
Conclusion: Overall, bioinformatics tools combined with omics techniques have been extensively used to scientifically support the ancient practice of TCM to be scientific and international through the acquisition, storage and analysis of biomedical data.
DNA methylation is an epigenetic mechanism that orchestrates many of the abnormal gene expression changes seen in cancer without altering the actual genomic DNA sequences. Emerging evidence support that aberrant DNA methylation is an archetypal hallmark of cancer, and hypermethylation-mediated inactivation of tumor suppressor genes as well as hypomethylation-mediated activation of prometastatic genes are common attributes of cancer cells. Since methylation of DNA is reversible, targeting the methylome may serve as a suitable anti-cancer strategy. Several epigenetic drugs especially the ones which target the key enzyme in DNA methylation process, the DNA-methyltransferases (DNMTs), have shown promising results in clinical trials. Two DNMT inhibitors, 5-azacytidine (Vidaza ®) and 5-aza-2′-deoxycytidine (Decitabine, Dacogen ®), have already been approved by the Food and Drug Administration (FDA) for treating several types of cancer. Nevertheless, targeting hypermethylation through the use of DNMT inhibitors can also activate several prometastatic genes apart from the activation of tumor suppressor genes. This may lead to metastasis which is the primary cause of morbidity and mortality associated with solid tumors like breast cancer. So the anti-cancer strategies require a balance between the activation of tumor suppressor genes and repression of prometastatic genes to collectively block tumor growth and metastasis. This review describes some of the common methylation abnormalities seen in promoters of cancer-associated genes, the mechanism of action of various hypermethylation and hypomethylation inhibitors, the potential benefits and challenges of using them as anti-cancer therapeutic agents in general and for patients with breast cancer in particular as monotherapy or in combination settings.
