Identification of Antineoplastic Targets with Systems Approaches, Using Resveratrol as an In-Depth Case Study

The identification and validation of novel drug–target combinations are key steps in the drug discovery processes. Cancer is a complex disease that involves several genetic and environmental factors. High-throughput omics technologies are now widely available, however the integration of multi-omics data to identify viable anticancer drug-target combinations, that allow for a better clinical outcome when considering the efficacy-toxicity spectrum, is challenging. This review article provides an overview of systems approaches which help to integrate a broad spectrum of technologies and data. We focus on network approaches and investigate anticancer mechanism and biological targets of resveratrol using reverse pharmacophore mapping as an in-depth case study. The results of this case study demonstrate the use of systems approaches for a better understanding of the behavior of small molecule inhibitors in receptor binding sites. The presented network analysis approach helps in formulating hypotheses and provides mechanistic insights of resveratrol in neoplastic transformations.

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The Protein Kinase, RSK2, A Novel Drug Target for Breast Cancer

10.21236/ada437856 ◽

2005 ◽

Author(s):

Deborah A. Lannigan

Keyword(s):

Breast Cancer ◽

Protein Kinase ◽

Drug Target ◽

Novel Drug

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Novel Nano Carriers for the Treatment of Progressive Auto Immune Disease Rheumatoid Arthritis

Current Pharmaceutical Design ◽

10.2174/1381612826666201021130146 ◽

2020 ◽

Vol 26 ◽

Author(s):

Ritu Mishra ◽

Swati Gupta

Keyword(s):

Rheumatoid Arthritis ◽

Drug Delivery ◽

Autoimmune Disease ◽

Drug Delivery Systems ◽

Clinical Manifestations ◽

Adaptive Immune Response ◽

Delivery Systems ◽

Current Therapy ◽

Genetic And Environmental Factors ◽

Novel Drug

Background: Rheumatoid arthritis (RA) is the most common occurring progressive, autoimmune disease, affecting 1% of the population and the ratio of affected women is three times as compared to men in most developing countries. Clinical manifestations of RA are the presence of anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) in blood, tendered joints and soreness of the muscles. Some other factors which may lead to chronic inflammation are genetic and environmental factors as well as adaptive immune response. Several conventional drugs are available for the treatment of RA but have their own drawbacks which can be overcome by the use of novel drug delivery systems. : The objective of the present review is to focus on the molecular pathogenesis of the disease and its current conventional treatment with special reference to the role of novel drug delivery systems encapsulating anti rheumatic drugs and herbal drugs in passive and receptor mediated active targeting against RA. On reviewing the conventional and current therapeutics agains RA, we conclude that, although the current therapy for the treatment of RA is capable enough, yet more advances in the field of targeted drug delivery will sanguinely result in effective and appropriate treatment of this autoimmune disease.

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Application of Cryo-Electron Microscopy on Drug Discovery

Microscopy and Microanalysis ◽

10.1017/s143192762101120x ◽

2021 ◽

Vol 27 (S1) ◽

pp. 3250-3250

Author(s):

Viswanath Vittaladevaram ◽

Kranthi Kuruti

Keyword(s):

Electron Microscopy ◽

Protein Complexes ◽

Lead Discovery ◽

Biologically Relevant ◽

Biological Targets ◽

3 Dimensional ◽

Drug Molecules ◽

Cryo Electron Microscopy ◽

Therapeutic Molecules ◽

Novel Drug

AbstractThe key aspect for development of novel drug molecules is to perform structural determination of target molecule associated with its ligand. One such tool that provides insights towards structure of molecule is Cryo-electron microscopy which covers biological targets that are intractable. Examination of proteins can be carried out in native state, as the samples are frozen at -175 degree Celsius i.e. cryogenic temperatures. In addition to this, there were no limits for molecular and functional structures of proteins that can be imagined in 3-dimensional form. This includes ligands which unravel mechanisms that are biologically relevant. This will enable to better understand the mechanisms that are used for development of new therapeutics. Application of Cryo-electron microscopy is not limited to protein complexes and is considered as non-specific. Intervention of Cryo-EM would allow to analyse the structures and also able to dissect the interaction with therapeutic molecules. The study determines the usage of cryo-EM for providing resolutions that are acceptable for lead discovery. It also provides support for lead optimization and also for discovery of vaccines and therapeutics.

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Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease

Scientific Reports ◽

10.1038/s41598-021-92701-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pusheng Quan ◽

Kai Wang ◽

Shi Yan ◽

Shirong Wen ◽

Chengqun Wei ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drug Target ◽

Target Genes ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Control Group ◽

Drug Candidates ◽

Novel Drug

AbstractThis study aimed to identify potential novel drug candidates and targets for Parkinson’s disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

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4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

Microorganisms ◽

10.3390/microorganisms9040826 ◽

2021 ◽

Vol 9 (4) ◽

pp. 826

Author(s):

Dorien Mabille ◽

Camila Cardoso Santos ◽

Rik Hendrickx ◽

Mathieu Claes ◽

Peter Takac ◽

...

Keyword(s):

Mode Of Action ◽

Drug Target ◽

Drug Targets ◽

De Novo ◽

Treatment Options ◽

Adenosine Kinase ◽

Nucleoside Analogues ◽

Purine Salvage ◽

Interacting Protein ◽

Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

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Drug–target prediction utilizing heterogeneous bio-linked network embeddings

Briefings in Bioinformatics ◽

10.1093/bib/bbz147 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nansu Zong ◽

Rachael Sze Nga Wong ◽

Yue Yu ◽

Andrew Wen ◽

Ming Huang ◽

...

Keyword(s):

Drug Target ◽

Target Prediction ◽

Machine Learning Algorithms ◽

Association Mining ◽

Drug Target Prediction ◽

Specific Prediction ◽

Series Of Experiments ◽

Inference Methods ◽

Novel Drug ◽

Prediction Strategy

Abstract To enable modularization for network-based prediction, we conducted a review of known methods conducting the various subtasks corresponding to the creation of a drug–target prediction framework and associated benchmarking to determine the highest-performing approaches. Accordingly, our contributions are as follows: (i) from a network perspective, we benchmarked the association-mining performance of 32 distinct subnetwork permutations, arranging based on a comprehensive heterogeneous biomedical network derived from 12 repositories; (ii) from a methodological perspective, we identified the best prediction strategy based on a review of combinations of the components with off-the-shelf classification, inference methods and graph embedding methods. Our benchmarking strategy consisted of two series of experiments, totaling six distinct tasks from the two perspectives, to determine the best prediction. We demonstrated that the proposed method outperformed the existing network-based methods as well as how combinatorial networks and methodologies can influence the prediction. In addition, we conducted disease-specific prediction tasks for 20 distinct diseases and showed the reliability of the strategy in predicting 75 novel drug–target associations as shown by a validation utilizing DrugBank 5.1.0. In particular, we revealed a connection of the network topology with the biological explanations for predicting the diseases, ‘Asthma’ ‘Hypertension’, and ‘Dementia’. The results of our benchmarking produced knowledge on a network-based prediction framework with the modularization of the feature selection and association prediction, which can be easily adapted and extended to other feature sources or machine learning algorithms as well as a performed baseline to comprehensively evaluate the utility of incorporating varying data sources.

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Vitamin D Receptor is a Novel Drug Target for Ovarian Cancer Treatment

Current Cancer Drug Targets ◽

10.2174/156800906776842939 ◽

2006 ◽

Vol 6 (3) ◽

pp. 229-244 ◽

Cited By ~ 25

Author(s):

Xiaohui Zhang ◽

Santo Nicosia ◽

Wenlong Bai

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Cancer Treatment ◽

Vitamin D Receptor ◽

Drug Target ◽

Novel Drug

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Association of angiotensin II type 1-receptor gene polymorphisms with the risk of developing hypertension in Mexican individuals

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311419175 ◽

2011 ◽

Vol 13 (1) ◽

pp. 133-140 ◽

Cited By ~ 11

Author(s):

Nancy Martínez-Rodríguez ◽

Carlos Posadas-Romero ◽

Guillermo Cardoso ◽

José Manuel Pérez-Rodríguez ◽

Nonanzit Pérez-Hernández ◽

...

Keyword(s):

Angiotensin Ii ◽

Gene Polymorphisms ◽

Complex Disease ◽

Receptor Gene ◽

Renin Angiotensin System ◽

Similar Distribution ◽

Increased Risk ◽

Receptor Gene Polymorphisms ◽

Genetic And Environmental Factors

Introduction: Hypertension is a complex disease in which a significant interaction between genetic and environmental factors takes place. The renin–angiotensin system plays an important role regulating blood pressure to maintain homeostasis and vascular tone. In the present work, the role of angiotensin II type 1-receptor (AGTR1) gene polymorphisms as susceptibility markers for hypertension was evaluated. Materials and methods: Five polymorphisms in the AGTR1 gene were genotyped by 5′ exonuclease TaqMan genotyping assays in 239 hypertensive and 371 non-hypertensive individuals. Results: A similar distribution of rs275651, rs275652, rs275653, and rs5183 polymorphisms was observed in both studied groups. Different distribution of rs5182 genotypes was observed between the studied groups ( p = 0.016). According to the co-dominant model, individuals with rs5182 CC genotype have a 1.83-fold increased risk of developing hypertension ( p = 0.009). Polymorphisms were distributed in two blocks: block 1 included the rs275651, rs275652, and rs275653 polymorphisms, whereas block 2 included the rs5183 and rs5182 polymorphisms. Individuals with hypertension showed increased frequency of ‘ CA’ haplotype of block 2 when compared to non-hypertensive individuals ( p = 0.015, odds ratio = 1.33). Conclusion: The results suggest that the rs5182 gene polymorphism could be involved in the risk of developing hypertension in Mexican individuals.

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