A Target Repurposing Approach Identifies N-myristoyltransferase as a New Candidate Drug Target in Filarial Nematodes

Background: Wolbachia is the most common endosymbiotic bacteria in insectborne parasites and it is the most common reproductive parasite in the world. Wolbachia has been found worldwide in numerous arthropod and parasite species, including insects, terrestrial isopods, spiders, mites and filarial nematodes. There is a complicated relationship between Wolbachia and its hosts and in some cases, they create a mutual relationship instead of a parasitic relationship. Some species are not able to reproduce in the absence of infection with Wolbachia. Thus, the use of existing strains of Wolbachia bacteria offers a potential strategy for the control of the population of mosquitoes and other pests and diseases. Methods: We searched ten databases and reviewed published papers regarding the role of Wolbachia as a promising drug target and emerging biological control agents of parasitic diseases between 1996 and 2017 (22 years) were considered eligible. Also, in the current study several patents (WO008652), (US7723062), and (US 0345249 A1) were reviewed. Results: Endosymbiotic Wolbachia bacteria, which are inherited from mothers, is transmitted to mosquitoes and interferes with pathogen transmission. They can change the reproduction of their host. Wolbachia is transmitted through the cytoplasm of eggs and have evolved different mechanisms for manipulating the reproduction of its hosts, including the induction of reproductive incompatibility, parthenogenesis, and feminization. The extensive effects of Wolbachia on reproduction and host fitness have made Wolbachia the issue of growing attention as a potential biocontrol agent. Conclusion: Wolbachia has opened a new window to design a costly, potent and ecofriendly drug target for effective treatment and elimination of vector-borne parasitic diseases.

Download Full-text

Genetic and Chemical Evaluation of Trypanosoma brucei Oleate Desaturase as a Candidate Drug Target

PLoS ONE ◽

10.1371/journal.pone.0014239 ◽

2010 ◽

Vol 5 (12) ◽

pp. e14239 ◽

Cited By ~ 10

Author(s):

Andrés Alloatti ◽

Shreedhara Gupta ◽

Melisa Gualdrón-López ◽

Mariana Igoillo-Esteve ◽

Paul A. Nguewa ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Drug Target ◽

Oleate Desaturase ◽

Chemical Evaluation ◽

Candidate Drug

Download Full-text

Biochemical Characterization of Glutamate Racemase—A New Candidate Drug Target against Burkholderia cenocepacia Infections

PLoS ONE ◽

10.1371/journal.pone.0167350 ◽

2016 ◽

Vol 11 (11) ◽

pp. e0167350 ◽

Cited By ~ 6

Author(s):

Aygun Israyilova ◽

Silvia Buroni ◽

Federico Forneris ◽

Viola Camilla Scoffone ◽

Namiq Q. Shixaliyev ◽

...

Keyword(s):

Drug Target ◽

Biochemical Characterization ◽

Burkholderia Cenocepacia ◽

Glutamate Racemase ◽

Candidate Drug

Download Full-text

Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms19113579 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3579 ◽

Cited By ~ 2

Author(s):

Tae-Woo Choi ◽

Jeong Cho ◽

Joohong Ahnn ◽

Hyun-Ok Song

Keyword(s):

Virtual Screening ◽

Drug Target ◽

Structural Features ◽

New Drugs ◽

C Elegans ◽

Good Target ◽

Filarial Nematodes ◽

Inhibitory Potential ◽

Considerable Morbidity ◽

Cuticle Development

Lymphatic filariasis and onchocerciasis caused by filarial nematodes are important diseases leading to considerable morbidity throughout tropical countries. Diethylcarbamazine (DEC), albendazole (ALB), and ivermectin (IVM) used in massive drug administration are not highly effective in killing the long-lived adult worms, and there is demand for the development of novel macrofilaricidal drugs affecting new molecular targets. A Ca2+ binding protein, calumenin, was identified as a novel and nematode-specific drug target for filariasis, due to its involvement in fertility and cuticle development in nematodes. As sterilizing and killing effects of the adult worms are considered to be ideal profiles of new drugs, calumenin could be an eligible drug target. Indeed, the Caenorhabditis elegans mutant model of calumenin exhibited enhanced drug acceptability to both microfilaricidal drugs (ALB and IVM) even at the adult stage, proving the roles of the nematode cuticle in efficient drug entry. Molecular modeling revealed that structural features of calumenin were only conserved among nematodes (C. elegans, Brugia malayi, and Onchocerca volvulus). Structural conservation and the specificity of nematode calumenins enabled the development of drugs with good target selectivity between parasites and human hosts. Structure-based virtual screening resulted in the discovery of itraconazole (ITC), an inhibitor of sterol biosynthesis, as a nematode calumenin-targeting ligand. The inhibitory potential of ITC was tested using a nematode mutant model of calumenin.

Download Full-text

Proteome mining for drug target identification in Listeria monocytogenes strain EGD-e and structure-based virtual screening of a candidate drug target penicillin binding protein 4

Journal of Microbiological Methods ◽

10.1016/j.mimet.2015.01.011 ◽

2015 ◽

Vol 111 ◽

pp. 9-18 ◽

Cited By ~ 11

Author(s):

Aditya Narayan Sarangi ◽

Mohtasim Lohani ◽

Rakesh Aggarwal

Keyword(s):

Listeria Monocytogenes ◽

Virtual Screening ◽

Drug Target ◽

Target Identification ◽

Binding Protein ◽

Penicillin Binding Protein ◽

Candidate Drug ◽

Drug Target Identification

Download Full-text

Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR𝛾 signaling

10.1101/2021.04.15.439941 ◽

2021 ◽

Author(s):

Nika Schuermans ◽

Salima El Chehadeh ◽

Dimitri Hemelsoet ◽

Elke Bogaert ◽

Elke Debackere ◽

...

Keyword(s):

Insulin Resistance ◽

Arachidonic Acid ◽

Drug Target ◽

Loss Of Function ◽

Membrane Phospholipids ◽

Partial Lipodystrophy ◽

Severe Insulin Resistance ◽

Diet Induced Obesity ◽

Candidate Drug ◽

And Function

PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.

Download Full-text

Identifying potential drug targets and candidate drugs for COVID-19: biological networks and structural modeling approaches

F1000Research ◽

10.12688/f1000research.50850.1 ◽

2021 ◽

Vol 10 ◽

pp. 127

Author(s):

Gurudeeban Selvaraj ◽

Satyavani Kaliamurthi ◽

Gilles H. Peslherbe ◽

Dong-Qing Wei

Keyword(s):

Signaling Pathways ◽

Drug Target ◽

Drug Targets ◽

Structural Modeling ◽

Protein Docking ◽

Receptor Signaling ◽

Potential Drug ◽

Ppi Network ◽

Candidate Drug ◽

Potential Drug Targets

Background: Coronavirus (CoV) is an emerging human pathogen causing severe acute respiratory syndrome (SARS) around the world. Earlier identification of biomarkers for SARS can facilitate detection and reduce the mortality rate of the disease. Thus, by integrated network analysis and structural modeling approach, we aimed to explore the potential drug targets and the candidate drugs for coronavirus medicated SARS. Methods: Differentially expression (DE) analysis of CoV infected host genes (HGs) expression profiles was conducted by using the Limma. Highly integrated DE-CoV-HGs were selected to construct the protein-protein interaction (PPI) network. Results: Using the Walktrap algorithm highly interconnected modules include module 1 (202 nodes); module 2 (126 nodes) and module 3 (121 nodes) modules were retrieved from the PPI network. MYC, HDAC9, NCOA3, CEBPB, VEGFA, BCL3, SMAD3, SMURF1, KLHL12, CBL, ERBB4, and CRKL were identified as potential drug targets (PDTs), which are highly expressed in the human respiratory system after CoV infection. Functional terms growth factor receptor binding, c-type lectin receptor signaling, interleukin-1 mediated signaling, TAP dependent antigen processing and presentation of peptide antigen via MHC class I, stimulatory T cell receptor signaling, and innate immune response signaling pathways, signal transduction and cytokine immune signaling pathways were enriched in the modules. Protein-protein docking results demonstrated the strong binding affinity (-314.57 kcal/mol) of the ERBB4-3cLpro complex which was selected as a drug target. In addition, molecular dynamics simulations indicated the structural stability and flexibility of the ERBB4-3cLpro complex. Further, Wortmannin was proposed as a candidate drug to ERBB4 to control SARS-CoV-2 pathogenesis through inhibit receptor tyrosine kinase-dependent macropinocytosis, MAPK signaling, and NF-kb singling pathways that regulate host cell entry, replication, and modulation of the host immune system. Conclusion: We conclude that CoV drug target “ERBB4” and candidate drug “Wortmannin” provide insights on the possible personalized therapeutics for emerging COVID-19.

Download Full-text

Discovering Protein Drug Targets Using Knowledge Graph Embeddings

Bioinformatics ◽

10.1093/bioinformatics/btz600 ◽

2019 ◽

Cited By ~ 3

Author(s):

Sameh K Mohamed ◽

Vít Nováček ◽

Aayah Nounu

Keyword(s):

Drug Target ◽

Drug Targets ◽

Knowledge Bases ◽

Knowledge Graph ◽

Biomedical Knowledge ◽

False Positive Prediction ◽

Benchmark Tests ◽

Drug Mechanism ◽

Candidate Drug ◽

Machine Readable

Abstract Motivation Computational approaches for predicting drug-target interactions (DTIs) can provide valuable insights into the drug mechanism of action. DTI predictions can help to quickly identify new promising (on-target) or unintended (off-target) effects of drugs. However, existing models face several challenges. Many can only process a limited number of drugs and/or have poor proteome coverage. The current approaches also often suffer from high false positive prediction rates. Results We propose a novel computational approach for predicting drug target proteins. The approach is based on formulating the problem as a link prediction in knowledge graphs (robust, machine-readable representations of networked knowledge). We use biomedical knowledge bases to create a knowledge graph of entities connected to both drugs and their potential targets. We propose a specific knowledge graph embedding model, TriModel, to learn vector representaions (i.e. embeddings) for all drugs and targets in the created knowledge graph. These representations are consequently used to infer candidate drug target interactions based on their scores computed by the trained TriModel model. We have experimentally evaluated our method using computer simulations and compared it to five existing models. This has shown that our approach outperforms all previous ones in terms of both area under ROC and precision-recall curves in standard benchmark tests. Availability The data, predictions, and models are available at: drugtargets.insight-centre.org

Download Full-text

Tau Pathology

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch010 ◽

2019 ◽

pp. 217-234

Author(s):

Ankush Bansal ◽

Mehul Salaria ◽

Tiratha Raj Singh

Keyword(s):

Neurofibrillary Tangles ◽

Tau Protein ◽

Neurodegenerative Disorders ◽

Drug Target ◽

Therapeutic Implication ◽

Regulation Mechanism ◽

Tau Pathology ◽

Microtubule Stability ◽

Candidate Drug ◽

Comprehensive Study

A number of neurodegenerative disorders (NDs) are usually referred as tauopathies and characterized by the disappearance or disintegration of tau protein from microtubules. Alzheimer's disease (AD), Pick's disease (PiD), Parkinson's disease (PD) are directly or indirectly associated with tauopathy. Tau is a protein which is usually associated with microtubule. Microtubules are the backbone of neurons, and tau provides a support to microtubule stability. Hyperphosphorylation of tau leads to its separation from microtubule, consequently forming neurofibrillary tangles and resulting in a condition of dementia. Therapeutic implication on tauopathy is symptomatic as there is no exact regulation mechanism known till date. This chapter helps in the comprehensive study of biomarkers and pathways involved in tauopathy to decipher the complexity of the system, resulting in candidate drug target for the management of NDs.

Download Full-text