scholarly journals Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Annie N. Cowell ◽  
Elizabeth A. Winzeler
Keyword(s):  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Trna Synthetase ◽  
Parasite Development ◽  
Major Advance ◽  
Liver Stage ◽  
Target Deconvolution ◽  
Novel Targets

Abstract A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and gametocytes. A primary method for drug target deconvolution in Plasmodium falciparum is in vitro evolution of compound-resistant parasites followed by whole-genome scans. Several of the most promising antimalarial drug targets, such as translation elongation factor 2 (eEF2) and phenylalanine tRNA synthetase (PheRS), have been identified or confirmed using this method. One drawback of this method is that if a mutated gene is uncharacterized, a substantial effort may be required to determine whether it is a drug target, a drug resistance gene, or if the mutation is merely a background mutation. Thus, the availability of high-throughput, functional genomic datasets can greatly assist with target deconvolution. Studies mapping genome-wide essentiality in P. falciparum or performing transcriptional profiling of the host and parasite during liver-stage infection with P. berghei have identified potentially druggable pathways. Advances in mapping the epigenomic regulation of the malaria parasite genome have also enabled the identification of key processes involved in parasite development. In addition, the examination of the host genome during infection has identified novel gene candidates associated with susceptibility to severe malaria. Here, we review recent studies that have used omics-based methods to identify novel targets for interventions against protozoan parasites, focusing on malaria, and we highlight the advantages and limitations of the approaches used. These approaches have also been extended to other protozoan pathogens, including Toxoplasma, Trypanosoma, and Leishmania spp., and these studies highlight how drug discovery efforts against these pathogens benefit from the utilization of diverse omics-based methods to identify promising drug targets.

scholarly journals Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tabish Qidwai ◽  
Farrukh Jamal ◽  
Mohd Y. Khan ◽  
Bechan Sharma
Keyword(s):  
Antimalarial Drug ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Biosynthetic Pathway ◽  
Comprehensive Analysis ◽  
Isoprenoid Biosynthesis ◽  
Biosynthesis Pathway ◽  
Novel Targets

Emergence of rapid drug resistance to existing antimalarial drugs inPlasmodium falciparumhas created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

scholarly journals Open-source chemogenomic data-driven algorithms for predicting drug–target interactions

2018 ◽  
Vol 20 (4) ◽  
pp. 1465-1474 ◽  
Author(s):  
Ming Hao ◽  
Stephen H Bryant ◽  
Yanli Wang
Keyword(s):  
Drug Discovery ◽  
Human Genome ◽  
High Throughput Screening ◽  
Drug Target ◽  
Drug Targets ◽  
Drug Repositioning ◽  
Research Field ◽  
Data Driven ◽  
Source Codes ◽  
Novel Technologies

AbstractWhile novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug–target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred.

scholarly journals Unbiased Identification of Extracellular Protein–Protein Interactions for Drug Target and Biologic Drug Discovery

2021 ◽  
Author(s):  
Shengya Cao ◽  
Nadia Martinez-Martin
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Target ◽  
Drug Targets ◽  
Extracellular Protein ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Drug Target Discovery ◽  
Technological Improvements ◽  
Targeted Drug Discovery

Technological improvements in unbiased screening have accelerated drug target discovery. In particular, membrane-embedded and secreted proteins have gained attention because of their ability to orchestrate intercellular communication. Dysregulation of their extracellular protein–protein interactions (ePPIs) underlies the initiation and progression of many human diseases. Practically, ePPIs are also accessible for modulation by therapeutics since they operate outside of the plasma membrane. Therefore, it is unsurprising that while these proteins make up about 30% of human genes, they encompass the majority of drug targets approved by the FDA. Even so, most secreted and membrane proteins remain uncharacterized in terms of binding partners and cellular functions. To address this, a number of approaches have been developed to overcome challenges associated with membrane protein biology and ePPI discovery. This chapter will cover recent advances that use high-throughput methods to move towards the generation of a comprehensive network of ePPIs in humans for future targeted drug discovery.

scholarly journals Targeting tRNA-Synthetase Interactions towards Novel Therapeutic Discovery Against Eukaryotic Pathogens

2019 ◽  
Author(s):  
Paul Kelly ◽  
Fatemeh Hadi-Nezhad ◽  
Dennis Liu ◽  
Travis J. Lawrence ◽  
Roger G. Linington ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Broad Spectrum ◽  
Marine Natural Products ◽  
Drug Targets ◽  
Leishmania Major ◽  
Trna Synthetase ◽  
Cross Reactivity ◽  
Protein Synthesis Inhibitors ◽  
Macromolecular Interactions

AbstractThe development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and eight clades of trypanosomes, identifying parasite-specific informative features (including base-pairs and base mis-pairs) that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. These findings support a systems biology model in which combination chemotherapies that target multiple tRNA-synthetase interactions should be comparatively less prone to the emergence of resistance than conventional single drug therapies.Author SummaryTrypanosome parasites pose a significant health risk worldwide. Conventional drug development strategies have proven challenging given the high conservation between humans and pathogens, with off-target toxicity being a common problem. Protein synthesis inhibitors have historically been an attractive target for antimicrobial discovery against bacteria, and more recently for eukaryotic pathogens. Here we propose that exploiting pathogen-specific tRNA-synthetase interactions offers the potential for highly targeted drug discovery. To this end, we improved tRNA gene annotations in trypanosome genomes, identified functionally informative trypanosome-specific tRNA features, and showed that these features are highly conserved over approximately 250 million years of trypanosome evolution. Highlighting the species-specific and broad-spectrum potential of our approach, we identified natural product inhibitors against the parasite translational machinery that have no effect on the homologous human enzyme.

scholarly journals Reference gene analysis and its use for kinase expression profiling in Fasciola hepatica

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hicham Houhou ◽  
Oliver Puckelwaldt ◽  
Christina Strube ◽  
Simone Haeberlein
Keyword(s):  
Reference Genes ◽  
Drug Targets ◽  
Fasciola Hepatica ◽  
Expression Patterns ◽  
Housekeeping Gene ◽  
Trna Synthetase ◽  
Parasite Development ◽  
Mammalian Host ◽  
Life Stages

Abstract The liver fluke Fasciola hepatica causes fasciolosis, a foodborne zoonosis affecting humans and livestock worldwide. A reliable quantification of gene expression in all parasite life stages relevant for targeting by anthelmintics in the mammalian host is fundamental. The aim of this study was to define a set of stably expressed reference genes for qRT-PCR in Fasciola studies. We determined the expression stabilities of eight candidate reference genes by the algorithms NormFinder, geNorm, BestKeeper, and comparative ΔCT method. The most stably expressed reference genes for the comparison of intra-mammalian life stages were glutamyl-prolyl-tRNA synthetase (Fheprs) and tubulin-specific chaperone D (Fhtbcd). The two best reference genes for analysis of in vitro-cultured juveniles were Fhtbcd and proteasome subunit beta type-7 (Fhpsmb7). These genes should replace the housekeeping gene gapdh which is used in most Fasciola studies to date, but in fact was differentially expressed in our analysis. Based on the new reference genes, we quantified expression of five kinases (Abl1, Abl2, PKC, Akt1, Plk1) discussed as targets in other parasitic flatworms. Distinct expression patterns throughout development were revealed and point to interesting biological functions. We like to motivate using this set of validated reference genes for future F. hepatica research, such as studies on drug targets or parasite development.

Essential gene identification and drug target prioritization in Leishmania species

2014 ◽  
Vol 10 (5) ◽  
pp. 1184-1195 ◽  
Author(s):  
M. L. Stanly Paul ◽  
Amandeep Kaur ◽  
Ankit Geete ◽  
M. Elizabeth Sobhia
Keyword(s):  
Drug Discovery ◽  
Drug Target ◽  
Drug Targets ◽  
Essential Gene ◽  
Leishmania Species ◽  
Gene Identification ◽  
Specific Drug

New stage specific drug targets for contemporary drug discovery for leishmaniasis.

scholarly journals Transforming TRP Channel Drug Discovery Using Medium-Throughput Electrophysiological Assays

2013 ◽  
Vol 19 (3) ◽  
pp. 468-477 ◽  
Author(s):  
Jean-Marie Chambard ◽  
Eric Tagat ◽  
Philippe Boudeau ◽  
Michel Partiseti
Keyword(s):  
Drug Discovery ◽  
Drug Target ◽  
Drug Targets ◽  
Transient Receptor Potential ◽  
Inflammatory Diseases ◽  
Receptor Potential ◽  
Target Class ◽  
Screening Assays ◽  
Transient Receptor ◽  
Almost All

Since the cloning of its first member in 1998, transient receptor potential (TRP) cation channels have become one of the most studied ion channel families in drug discovery. These channels, almost all calcium permeant, have been studied in many different (patho)-physiological and therapeutic areas as diverse as pain; neurodegenerative, cardiovascular, and inflammatory diseases; and cancer. At the same time, implementation of automated electrophysiology screening platforms has significantly increased the tractability of ion channels, mainly voltage gated, as drug targets. The work presented in this article shows the design and validation of TRP screening assays using the IonWorks Quattro platform (Molecular Devices, Sunnyvale, CA), allowing a significant increase in throughput to support drug discovery programs. This new player has a direct impact on resources and timelines by prioritizing potential candidates and reducing the number of molecules requiring final testing by manual patch-clamp, which is still today the gold standard technology for this challenging drug target class.

Exploring Novel Targets for Antimalarial Drug Discovery: Plasmodial Protein Kinases

2010 ◽  
Vol 10 (3) ◽  
pp. 134-146 ◽  
Author(s):  
Dayadevi Jirage ◽  
Susan M. Keenan ◽  
Norman C. Waters
Keyword(s):  
Drug Discovery ◽  
Protein Kinases ◽  
Antimalarial Drug ◽  
Novel Targets

scholarly journals Target2drug : A Novel Programmatic Workflow to Automate in Silico Drug Discovery

2020 ◽  
Author(s):  
Ben Geoffrey A S ◽  
Rafal Madaj ◽  
Akhil Sanker ◽  
Pavan Preetham Valluri ◽  
Judith Gracia ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Computational Biology ◽  
In Silico ◽  
Drug Target ◽  
Drug Targets ◽  
Qsar Model ◽  
Learning Tools ◽  
Active Compounds ◽  
Qsar Modelling ◽  
Drug Leads

As the Big Data and Artificial Intelligence (AI) revolution continues to affect every area of our lives, it’s influence is also exerted in the areas of bioinformatics, computational biology and drug discovery. Machine/Deep Learning tools have been developed to predict compounds-drug target interactions and the vice-versa process of predicting target interactions for an compound. In our presented work, we report a programmatic tool, which incorporates many features of the bioinformatics, computational biology and AI-driven drug discovery revolutions into a single workflow assembly. When a user is required to identify drugs against a new drug target, the user provides target signatures in the form of amino acid sequence of the target or it’s corresponding nucleotide sequence as input to the tool and the tool carries out a BLAST protocol to identify known protein drug targets that are similar to the new target submitted by the user and collects data linked to the target involving, active compounds against the target, the activity value and molecular descriptors of active compounds to perform QSAR modelling and to generate drug leads with predictions from the validated QSAR model. The tool performs an In-Silico modelling to generate In-Silico interaction profiles of compounds generated as drug leads and the target and stores the results in the working folder of the user. To demonstrate the use of the tool, we have carried out a demonstration with the target signatures of the current pandemic causing virus, SARS-CoV 2. However the tool can be used against any target and is expected to help in growing our knowledge graph of targets and interacting compounds. <br>

scholarly journals A specific non-bisphosphonate inhibitor of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites

2017 ◽  
Author(s):  
Jolyn E. Gisselberg ◽  
Zachary Herrera ◽  
Lindsey Orchard ◽  
Manuel Llinás ◽  
Ellen Yeh
Keyword(s):  
Plasmodium Falciparum ◽  
Physicochemical Properties ◽  
Small Molecule ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Malaria Parasites ◽  
Starting Point

SummaryIsoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.

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