Serine Proteases of Malaria ParasitePlasmodium falciparum: Potential as Antimalarial Drug Targets

Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found inP. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. InP. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential ofP. falciparumserine proteases as antimalarial drug targets.

Download Full-text

Modeling Novel Putative Drugs and Vaccine Candidates against Tick-Borne Pathogens: A Subtractive Proteomics Approach

Veterinary Sciences ◽

10.3390/vetsci7030129 ◽

2020 ◽

Vol 7 (3) ◽

pp. 129

Author(s):

Abid Ali ◽

Shabir Ahmad ◽

Abdul Wadood ◽

Ashfaq U. Rehman ◽

Hafsa Zahid ◽

...

Keyword(s):

Drug Targets ◽

Effective Control ◽

Potential Drug ◽

Homologous Proteins ◽

Vaccine Candidates ◽

Target Proteins ◽

Subtractive Proteomics ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Ticks and tick-borne pathogens (TBPs) continuously causing substantial losses to the public and veterinary health sectors. The identification of putative drug targets and vaccine candidates is crucial to control TBPs. No information has been recorded on designing novel drug targets and vaccine candidates based on proteins. Subtractive proteomics is an in silico approach that utilizes extensive screening for the identification of novel drug targets or vaccine candidates based on the determination of potential target proteins available in a pathogen proteome that may be used effectively to control diseases caused by these infectious agents. The present study aimed to investigate novel drug targets and vaccine candidates by utilizing subtractive proteomics to scan the available proteomes of TBPs and predict essential and non-host homologous proteins required for the survival of these diseases causing agents. Subtractive proteome analysis revealed a list of fifteen essential, non-host homologous, and unique metabolic proteins in the complete proteome of selected pathogens. Among these therapeutic target proteins, three were excluded due to the presence in host gut metagenome, eleven were found to be highly potential drug targets, while only one was found as a potential vaccine candidate against TBPs. The present study may provide a foundation to design potential drug targets and vaccine candidates for the effective control of infections caused by TBPs.

Download Full-text

Using gene networks to drug target identification

Journal of Integrative Bioinformatics ◽

10.1515/jib-2005-14 ◽

2005 ◽

Vol 2 (1) ◽

pp. 48-57 ◽

Cited By ~ 10

Author(s):

Zhenran Jiang ◽

Yanhong Zhou

Keyword(s):

Gene Networks ◽

Drug Targets ◽

Gene Network ◽

Target Identification ◽

Biological Data ◽

Potential Drug ◽

Drug Target Identification ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Abstract The complete genome sequences have provided a plethora of potential drug targets. Gene network technique holds the promise of providing a conceptual framework for analysis of the profusion of biological data being generated on potential drug targets and providing insights to understand the biological regulatory mechanisms in diseases, which are playing an increasingly important role in searching for novel drug targets from the information contained in genomics. In this paper, we discuss some of the network-based approaches for identifying drug targets, with the emphasis on the gene network strategy. In addition, some of the relevant data resources and computational tools are given.

Download Full-text

Potential Drug Targets Identification against Clostridioides difficile (CD) and Characterization of Indispensable Proteins by a Subtractive Genomics Approach Followed by Virtual Screening

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210930160128 ◽

2021 ◽

Vol 18 ◽

Author(s):

Reaz Uddin ◽

Alina Arif

Keyword(s):

Drug Targets ◽

Drug Resistant ◽

Potential Drug ◽

Drug Candidates ◽

Subtractive Genomics ◽

Clostridioides Difficile ◽

Subtractive Genomics Approach ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Background: Clostridioides difficile (CD) is a multi-drug resistant, enteric pathogenic bacterium. The CD associated infections are the leading cause of nosocomial diarrhea that can further lead to pseudomembranous colitis up to a toxic mega-colon or sepsis with greater mortality and morbidity risks. The CD infection possess higher rates of recurrence due to its greater resistance against antibiotics. Considering its higher rates of recurrence, it has become a major burden on the healthcare facilities. Therefore, there is a dire need to identify novel drug targets to combat with the antibiotic resistance of Clostridioides difficile. Objective: To identify and propose new and novel drug targets against the Clostridioides difficile. Methods: In the current study, a computational subtractive genomics approach was applied to obtain a set of potential drug targets that exists in the multi-drug resistant strain of Clostridioides difficile. Here, the uncharacterized proteins were studied as potential drug targets. The methodology involved several bioinformatics databases and tools. The druggable proteins sequences were retrieved based on non-homology with host proteome and essentiality for the survival of the pathogen. The uncharacterized proteins were functionally characterized using different computational tools and sub-cellular localization was also predicted. The metabolic pathways were analyzed using KEGG database. Eventually, the druggable proteome has been fetched using sequence similarity with the already available drug targets present in DrugBank database. These druggable proteins were further explored for the structural details to identify drug candidates. Results : A priority list of potential drug targets was provided with the help of the applied method on complete proteome set of the C. difficile. Moreover, the drug like compounds have been screened against the potential drug targets to prioritize potential drug candidates. To facilitate the need for drug targets and therapies, the study proposed five potential protein drug targets out of which three proposed drug targets were subjected to homology modeling to explore their structural and functional activities. Conclusion: In conclusion, we proposed three unique, unexplored drug targets against C. difficile. The structure-based methods were applied and resulted in a list of top scoring compounds as potential inhibitors to proposed drug targets.

Download Full-text

Recent advances in the understanding and treatment of acute myeloid leukemia

F1000Research ◽

10.12688/f1000research.14116.1 ◽

2018 ◽

Vol 7 ◽

pp. 1196 ◽

Cited By ~ 24

Author(s):

Justin Watts ◽

Stephen Nimer

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Drug Targets ◽

Poor Prognosis ◽

Clinical Development ◽

New Drugs ◽

Recent Advances ◽

Novel Drug ◽

Novel Drug Targets ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease that has a poor prognosis. Recent advances in genomics and molecular biology have led to a greatly improved understanding of the disease. Until 2017, there had been no new drugs approved for AML in decades. Here, we review novel drug targets in AML with a focus on epigenetic-targeted therapies in pre-clinical and clinical development as well as the recent new drug approvals.

Download Full-text

Identification of Glucose-Dependent Insulin Secretion Targets in Pancreatic β Cells by Combining Defined-Mechanism Compound Library Screening and siRNA Gene Silencing

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057107313763 ◽

2008 ◽

Vol 13 (2) ◽

pp. 128-134 ◽

Cited By ~ 19

Author(s):

Weizhen Wu ◽

Jin Shang ◽

Yue Feng ◽

Chris M. Thompson ◽

Sarah Horwitz ◽

...

Keyword(s):

Insulin Secretion ◽

Drug Targets ◽

Target Identification ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Major Bottleneck ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate—specific phosphodiesterases, adrenoceptors, and Ca2+ channels), the authors find that several of the dopamine receptor ( DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation. ( Journal of Biomolecular Screening 2008;128-134)

Download Full-text

Metabolic pathway analysis in trypanosomes and malaria parasites

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.1040 ◽

2002 ◽

Vol 357 (1417) ◽

pp. 101-107 ◽

Cited By ~ 22

Author(s):

Alan H. Fairlamb

Keyword(s):

Drug Target ◽

Drug Targets ◽

Target Identification ◽

Potential Drug ◽

Metabolic Pathway Analysis ◽

Entire Genome ◽

Microbial Responses ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Identification of novel drug targets is required for the development of new classes of drugs to overcome drug resistance and replace less efficacious treatments. In theory, knowledge of the entire genome of a pathogen identifies every potential drug target in any given microbe. In practice, the sheer complexity and the inadequate or inaccurate annotation of genomic information makes target identification and selection somewhat more difficult. Analysis of metabolic pathways provides a useful conceptual framework for the identification of potential drug targets and also for improving our understanding of microbial responses to nutritional, chemical and other environmental stresses. A number of metabolic databases are available as tools for such analyses. The strengths and weaknesses of this approach are discussed.

Download Full-text

Identification of novel drug targets using model organisms

Microbiology Australia ◽

10.1071/ma09095 ◽

2009 ◽

Vol 30 (2) ◽

pp. 95

Author(s):

Anthony Brzoska ◽

Ryan Withers ◽

Kylie Turner ◽

Andrew Robinson ◽

Nick Dizon ◽

...

Keyword(s):

Drug Targets ◽

Acquired Resistance ◽

New Drugs ◽

Model Organisms ◽

Magic Bullet ◽

The Public ◽

Vancomycin Resistant ◽

Novel Drug ◽

General Community ◽

Novel Drug Targets

Antibiotic resistance is an endemic problem within hospitals worldwide, and is becoming an increasing problem within the general community. Traditionally, physicians and the public have relied on the belief that as bacteria acquired resistance to one antibiotic, new drugs would be made available that could be used to combat those infections. The appearance of vancomycin-resistant Enterococcus (VRE) infections in the 1990s, combined with the withdrawal of funding for antimicrobial drug discovery and development by big Pharma, has led to the realisation that we can no longer assume that all infections can be treated with a ?magic bullet?. Recent years have seen the emergence of infections that are resistant to all clinically available antibiotics, including newly released drugs such as tigecycline. The cupboard is bare. Or at least it is heading that way.

Download Full-text

IN SILICO IDENTIFICATION OF NOVEL DRUG TARGETS IN ACINETOBACTER BAUMANNII BY SUBTRACTIVE GENOMIC APPROACH

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i3.22105 ◽

2018 ◽

Vol 11 (3) ◽

pp. 230 ◽

Cited By ~ 3

Author(s):

Meenu Goyal ◽

Citu Citu ◽

Nidhi Singh

Keyword(s):

Acinetobacter Baumannii ◽

In Silico ◽

Metabolic Pathways ◽

Drug Targets ◽

Potential Drug ◽

Homologous Proteins ◽

Essential Proteins ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

Download Full-text