scholarly journals Prioritizing and modelling of putative drug target proteins of Candida albicans by system biology approach

2018 ◽  
Vol 65 (2) ◽  
pp. 209-218 ◽  
Author(s):  
Tariq Ismail ◽  
Nighat Fatima ◽  
Syed Aun Muhammad ◽  
Syed Saoud Zaidi ◽  
Nisar Rehman ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Drug Target ◽  
Drug Targets ◽  
Cellular Localization ◽  
Critical Role ◽  
Human Microbiome ◽  
Genomic Analysis ◽  
Cellular Systems ◽  
Gut Flora ◽  
Target Proteins

Candida albicans (C. albicans) is one of the major source of nosocomial infections in human which may prove fatal in 30% of cases. The hospital acquired infection is very difficult to affectively treat due to the presence of drug resistant pathogenic strains, therefore there is a need to find alternative drug targets to cure this infection. In silico and computational level frame work was used to prioritize and establish antifungal drug targets of Candida albicans. The identification of putative drug targets was based on acquiring completely 5090 annotated genes of Candida albicans from available databases which was categorized into essential and non-essential genes. The result indicated 9% proteins were essential that could become potential candidates for intervention which might result in pathogen death. We studied cluster of orthologs and the subtractive genomic analysis of these essential proteins against human genome as a reference to minimize the side effects. It was seen that 14% of Candidal proteins were evolutionary related to the human proteins while 86% are non-human homologs. In next step for the selection of compatible drug targets, the non-human homologs were sequentially compared to human microbiome data to minimize the potential effects against gut flora which accumulated to 38% of essential genome. The sub-cellular localization of these candidate proteins in fungal cellular systems exhibited that 80% are cytoplasmic, 10% are mitochondrial and remaining 10 % are associated with cell wall. The role of these non-human and non-gut flora putative target proteins in Candidal biological pathways was studied and on the basis of their integrated and critical role 4-proteins were selected for molecular modeling.  For drug designing and development, five quality and reliable protein models with more than 70% homology were constructed. Our study will be an effective framework for drug target identifications of pathogenic microbial strains and development of new therapies against these infections.

scholarly journals Revealing the Bacterial Butyrate Synthesis Pathways by Analyzing (Meta)genomic Data

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Marius Vital ◽  
Adina Chuang Howe ◽  
James M. Tiedje
Keyword(s):  
Gut Microbiota ◽  
Critical Role ◽  
Human Microbiome ◽  
Genomic Analysis ◽  
16S Rrna Gene Sequencing ◽  
Emerging Diseases ◽  
Rrna Gene ◽  
Data Set ◽  
Genome Database ◽  
Health And Disease

ABSTRACTButyrate-producing bacteria have recently gained attention, since they are important for a healthy colon and when altered contribute to emerging diseases, such as ulcerative colitis and type II diabetes. This guild is polyphyletic and cannot be accurately detected by 16S rRNA gene sequencing. Consequently, approaches targeting the terminal genes of the main butyrate-producing pathway have been developed. However, since additional pathways exist and alternative, newly recognized enzymes catalyzing the terminal reaction have been described, previous investigations are often incomplete. We undertook a broad analysis of butyrate-producing pathways and individual genes by screening 3,184 sequenced bacterial genomes from the Integrated Microbial Genome database. Genomes of 225 bacteria with a potential to produce butyrate were identified, including many previously unknown candidates. The majority of candidates belong to distinct families within theFirmicutes, but members of nine other phyla, especially fromActinobacteria,Bacteroidetes,Fusobacteria,Proteobacteria,Spirochaetes, andThermotogae, were also identified as potential butyrate producers. The established gene catalogue (3,055 entries) was used to screen for butyrate synthesis pathways in 15 metagenomes derived from stool samples of healthy individuals provided by the HMP (Human Microbiome Project) consortium. A high percentage of total genomes exhibited a butyrate-producing pathway (mean, 19.1%; range, 3.2% to 39.4%), where the acetyl-coenzyme A (CoA) pathway was the most prevalent (mean, 79.7% of all pathways), followed by the lysine pathway (mean, 11.2%). Diversity analysis for the acetyl-CoA pathway showed that the same few firmicute groups associated with severalLachnospiraceaeandRuminococcaceaewere dominating in most individuals, whereas the other pathways were associated primarily withBacteroidetes.IMPORTANCEMicrobiome research has revealed new, important roles of our gut microbiota for maintaining health, but an understanding of effects of specific microbial functions on the host is in its infancy, partly because in-depth functional microbial analyses are rare and publicly available databases are often incomplete/misannotated. In this study, we focused on production of butyrate, the main energy source for colonocytes, which plays a critical role in health and disease. We have provided a complete database of genes from major known butyrate-producing pathways, using in-depth genomic analysis of publicly available genomes, filling an important gap to accurately assess the butyrate-producing potential of complex microbial communities from “-omics”-derived data. Furthermore, a reference data set containing the abundance and diversity of butyrate synthesis pathways from the healthy gut microbiota was established through a metagenomics-based assessment. This study will help in understanding the role of butyrate producers in health and disease and may assist the development of treatments for functional dysbiosis.

scholarly journals Efficient Data Mining Algorithms for Screening Potential Proteins of Drug Target

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Qi Wang ◽  
JinCai Huang ◽  
YangHe Feng ◽  
JiaWei Fei
Keyword(s):  
Decision Trees ◽  
Drug Target ◽  
Drug Targets ◽  
Chemical Properties ◽  
Superior Performance ◽  
Target Proteins ◽  
Data Mining Algorithms ◽  
Open Access Database ◽  
Human Proteins ◽  
Physical And Chemical

The past few decades have witnessed the boom in pharmacology as well as the dilemma of drug development. Playing a crucial role in drug design, the screening of potential human proteins of drug targets from open access database with well-measured physical and chemical properties is a task of challenge but significance. In this paper, the screening of potential drug target proteins (DTPs) from a fine collected dataset containing 5376 unlabeled proteins and 517 known DTPs was researched. Our objective is to screen potential DTPs from the 5376 proteins. Here we proposed two strategies assisting the construction of dataset of reliable nondrug target proteins (NDTPs) and then bagging of decision trees method was employed in the final prediction. Such two-stage algorithms have shown their effectiveness and superior performance on the testing set. Both of the algorithms maintained higher recall ratios of DTPs, respectively, 93.5% and 97.4%. In one turn of experiments, strategy1-based bagging of decision trees algorithm screened about 558 possible DTPs while 1782 potential DTPs were predicted in the second algorithm. Besides, two strategy-based algorithms showed the consensus of the predictions in the results, with approximately 442 potential DTPs in common. These selected DTPs provide reliable choices for further verification based on biomedical experiments.

scholarly journals Detecting Drug-Target Binding in Cells using Fluorescence Activated Cell Sorting Coupled with Mass Spectrometry Analysis

2017 ◽  
Author(s):  
Kris Wilson ◽  
Scott P Webster ◽  
John P Iredale ◽  
Xiaozhong Zheng ◽  
Natalie Z Homer ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Mass Spectrometry Analysis ◽  
Protein Targets ◽  
Target Proteins ◽  
Spectrometry Analysis ◽  
Cellular Permeability ◽  
Target Binding ◽  
Hit Validation

AbstractThe assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity - the Toxicity-Affinity-Permeability-Selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.

scholarly journals TarDict: A RandomForestClassifier based software predicts drug-target interaction using SMILES

2021 ◽  
pp. bi202101
Author(s):  
Peter Habib ◽  
Alsamman Alsamman ◽  
Sameh Hassanein ◽  
Aladdin Hamwieh
Keyword(s):  
Machine Learning ◽  
Computational Model ◽  
Drug Target ◽  
Drug Targets ◽  
Cost Effective ◽  
New Drugs ◽  
Drug Target Discovery ◽  
Target Proteins ◽  
Biological Targets ◽  
Testing Dataset

The future of therapeutics depends on understanding the interaction between the chemical structure of the drug and the target protein that contributes to the etiology of the disease in order to improve drug discovery. Predicting the target of unknown drugs being investigated from already identified drug data is very important not only for understanding different processes of drug and molecular interactions but also for the development of new drugs. Using machine learning and published drug information we design an easy-to-use tool that predicts biological target proteins for medical drugs. TarDict is based on a chemical-simplified line-entry molecular input system called SMILES. It receives SMILES entries and returns a list of possible similar drugs as well as possible drug-targets. TarDict uses 20442 drug entries that have well-known biological targets to construct a prognostic computational model capable of predicting novel drug targets with an accuracy of 95%. We developed a machine learning approach to recommend target proteins to approved drug targets. We have shown that the proposed method is highly predictive on a testing dataset consisting of 4088 targets and 102 manually entered drugs. The proposed computational model is an efficient and cost-effective tool for drug target discovery and prioritization. Such novel tool could be used to enhance drug design, predict potential target and identify combination therapy crossroads.

scholarly journals The distinct biochemical property enables thymidylate kinase as a drug target and participates in pyrimidine drug sensitivity in Candida albicans

2018 ◽  
Author(s):  
Chang-Yu Huang ◽  
Yee-Chun Chen ◽  
Betty A. Wu-Hsieh ◽  
Jim-Min Fang ◽  
Zee-Fen Chang
Keyword(s):  
Candida Albicans ◽  
Drug Target ◽  
Essential Gene ◽  
Critical Role ◽  
Unmet Need ◽  
Biochemical Property ◽  
Drug Resistant ◽  
Potential Drug ◽  
Thymidylate Kinase ◽  
Human Enzyme

AbstractThe ability to overcome drug resistance in outbreaks of Candida albicans infection is an unmet need in health management. Here, we investigated CDC8, which encodes thymidylate kinase (TMPK), as a potential drug target for the treatment of C. albicans infection. In this study, we found that the specific region spanning amino acids 106-123, namely, the Ca-loop of C. albicans TMPK (CaTMPK) contributes to the hyperactivity of this enzyme compared to the human enzyme (hTMPK) and to the utilization of deoxyuridine monophosphate (dUMP)/ deoxy-5-Fluorouridine monophosphate (5-FdUMP) as a substrate. Notably, CaTMPK but not hTMPK enables dUTP/5-FdUTP-mediated DNA toxicity in yeast. CRISPR-mediated deletion of this Ca-loop in C. albicans demonstrated the critical role of this Ca-loop in fungal growth and susceptibility to 5-Fluorouridine (5-FUrd). Moreover, pathogenic and drug-resistant C. albicans clones were similarly sensitive to 5-FUrd. Thus, this study not only identified a target site for the development of CaTMPK-selective drugs but also revealed 5-FUrd to be a potential drug for the treatment of C. albicans infection.Author summaryThe emergence of drug-resistant C. albicans strains is a serious medical concern that may be addressed by targeting an essential fungal enzyme. CDC8 encodes thymidylate kinase (TMPK), which is the key enzyme required for dTTP synthesis and is an essential gene for yeast growth. Therefore, the differences of TMPK between human and C. albicans can be a potential drug targeting site. This study defines a specific Ca-loop unique to CaTMPK from C. albicans, contributing to hyper-activity over human enzyme (hTMPK). CRSPR-edited deletion of this loop also suppressed the growth of C. albicans. Moreover, we present evidence that this loop enables dUMP utilization by CaTMPK, but not hTMPK. CaTMPK is also capable of using 5-FdUMP as a substrate, which contributes to 5-FUrd-mediated toxicity. Importantly, we found that many drug resistant pathogenic C. albicans isolates from patients are sensitive to 5-FUrd, which has not been used as a drug against fungal infection.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

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

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.

scholarly journals Signal-mediated localization of Candida albicans pheromone response pathway components

2020 ◽  
Author(s):  
Anna Carolina Borges Pereira Costa ◽  
Raha Parvizi Omran ◽  
Chris Law ◽  
Vanessa Dumeaux ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Map Kinase ◽  
Nuclear Localization ◽  
Map Kinases ◽  
Critical Role ◽  
Cell Periphery ◽  
Pheromone Response ◽  
Pheromone Response Pathway ◽  
Localization Signal ◽  
In Cells

Abstract Candida albicans opaque cells release pheromones to stimulate cells of opposite mating type to activate their pheromone response pathway. Although this fungal pathogen shares orthologous proteins involved in the process with Saccharomyces cerevisiae, the pathway in each organism has unique characteristics. We have used GFP-tagged fusion proteins to investigate the localization of the scaffold protein Cst5, as well as the MAP kinases Cek1 and Cek2, during pheromone response in C. albicans. In wild-type cells, pheromone treatment directed Cst5-GFP to surface puncta concentrated at the tips of mating projections. These puncta failed to form in cells defective in either the Gα or β subunits. However, they still formed in response to pheromone in cells missing Ste11, but with the puncta distributed around the cell periphery in the absence of mating projections. These puncta were absent from hst7Δ/Δ cells, but could be detected in the ste11Δ/Δ hst7Δ/Δ double mutant. Cek2-GFP showed a strong nuclear localization late in the response, consistent with a role in adaptation, while Cek1-GFP showed a weaker, but early increase in nuclear localization after pheromone treatment. Activation loop phosphorylation of both Cek1 and Cek2 required the presence of Ste11. In contrast to Cek2-GFP, which showed no localization signal in ste11Δ/Δ cells, Cek1-GFP showed enhanced nuclear localization that was pheromone independent in the ste11Δ/Δ mutant. The results are consistent with CaSte11 facilitating Hst7-mediated MAP kinase phosphorylation and also playing a potentially critical role in both MAP kinase and Cst5 scaffold localization.

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