Metabolic Pathways as Drug Targets: Targeting the Sulphur Assimilatory Pathways of Yeast and Fungi for Novel Drug Discovery

The advancements of information technology and related processing techniques have created a fertile base for progress in many scientific fields and industries. In the fields of drug discovery and development, machine learning techniques have been used for the development of novel drug candidates. The methods for designing drug targets and novel drug discovery now routinely combine machine learning and deep learning algorithms to enhance the efficiency, efficacy, and quality of developed outputs. The generation and incorporation of big data, through technologies such as high-throughput screening and high through-put computational analysis of databases used for both lead and target discovery, has increased the reliability of the machine learning and deep learning incorporated techniques. The use of these virtual screening and encompassing online information has also been highlighted in developing lead synthesis pathways. In this review, machine learning and deep learning algorithms utilized in drug discovery and associated techniques will be discussed. The applications that produce promising results and methods will be reviewed.

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Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

Biomedicines ◽

10.3390/biomedicines4040027 ◽

2016 ◽

Vol 4 (4) ◽

pp. 27 ◽

Cited By ~ 12

Author(s):

Suhas Vasaikar ◽

Pooja Bhatia ◽

Partap Bhatia ◽

Koon Chu Yaiw

Keyword(s):

Drug Discovery ◽

Drug Targets ◽

Novel Drug ◽

Novel Drug Targets

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Reconstruction of Sugar Metabolic Pathways of Giardia lamblia

International Journal of Proteomics ◽

10.1155/2012/980829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Jian Han ◽

Lesley J. Collins

Keyword(s):

Giardia Lamblia ◽

Metabolic Pathways ◽

Drug Targets ◽

Sugar Metabolism ◽

Tca Cycle ◽

The Tca Cycle ◽

Glycolysis Pathway ◽

Bioinformatic Approaches ◽

Novel Drug ◽

Novel Drug Targets

Giardia lamblia is an “important” pathogen of humans, but as a diplomonad excavate it is evolutionarily distant from other eukaryotes and relatively little is known about its core metabolic pathways. KEGG, the widely referenced site for providing information of metabolism, does not yet include many enzymes from Giardia species. Here we identify Giardia’s core sugar metabolism using standard bioinformatic approaches. By comparing Giardia proteomes with known enzymes from other species, we have identified enzymes in the glycolysis pathway, as well as some enzymes involved in the TCA cycle and oxidative phosphorylation. However, the majority of enzymes from the latter two pathways were not identifiable, indicating the likely absence of these functionalities. We have also found enzymes from the Giardia glycolysis pathway that appear more similar to those from bacteria. Because these enzymes are different from those found in mammals, the host organisms for Giardia, we raise the possibility that these bacteria-like enzymes could be novel drug targets for treating Giardia infections.

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Challenges in Drug Discovery against Tuberculosis

10.5772/intechopen.97857 ◽

2021 ◽

Author(s):

Manish Dwivedi ◽

Priya Giri

Keyword(s):

Drug Discovery ◽

Drug Targets ◽

Vaccine Development ◽

Extensive Literature ◽

Antitubercular Drugs ◽

Inadequate Information ◽

Adolescents And Adults ◽

Potent Drug ◽

Novel Drug

Tuberculosis (TB) is one of the deadly diseases in the present era caused by Mycobacterium tuberculosis. Principally, this bacterium attacks the lungs, however, MTB Has been observed affecting any part of the human body including the kidney, spine, and brain. Drug-resistant progression and other associated properties of MTB become a major hurdle in drug discovery to fight against tuberculosis. Moreover, some of the challenging situations such as the low range of chemical agents, the time-consuming process of drug development, the shortage of predictive animal models, and inadequate information of the physicochemical evidence required for effective bacterial penetration, are additional hindrances for the pharmaceutical scientist. In the current chapter, we focus on challenges encountered during drug discovery and need to be overcome as M. tuberculosis has a substantial barrier in its lipid-containing cell wall to inhibit the influx of drugs which is the initial requirement of the drug to show its therapeutic effect. There is also an immediate need for efficient vaccine development which may show its effect on adolescents and adults along with infants. Investigation on key bacterial targets has been troublesome, in light of the vulnerability around the microenvironments found in vivo and subsequently, the importance of exceptional metabolic pathways. The manuscript is prepared after the extensive literature survey to explore the vigorous approaches in novel drug designing and in proposing potent drug targets. The re-engineering and repositioning of prominent antitubercular drugs are required to attain viable control.

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Bioinformatics in translational drug discovery

Bioscience Reports ◽

10.1042/bsr20160180 ◽

2017 ◽

Vol 37 (4) ◽

Cited By ~ 11

Author(s):

Sarah K. Wooller ◽

Graeme Benstead-Hume ◽

Xiangrong Chen ◽

Yusuf Ali ◽

Frances M.G. Pearl

Keyword(s):

Big Data ◽

Drug Discovery ◽

Pharmaceutical Industry ◽

Drug Targets ◽

Large Data ◽

Data Warehouses ◽

The Creation ◽

Novel Drug ◽

Novel Drug Targets ◽

Discovery Pipeline

Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated during all phases of drug discovery is enabling key challenges of the process to be addressed. Here, we highlight some of the areas in which bioinformatics resources and methods are being developed to support the drug discovery pipeline. These include the creation of large data warehouses, bioinformatics algorithms to analyse ‘big data’ that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and prediction of repositioning opportunities that use licensed drugs to treat additional indications.

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Subtractive Genomics Approach for Identification of Novel Therapeutic Drug Targets in Mycoplasma genitalium

Pathogens ◽

10.3390/pathogens10080921 ◽

2021 ◽

Vol 10 (8) ◽

pp. 921

Author(s):

Abiodun Joseph Fatoba ◽

Moses Okpeku ◽

Matthew Adekunle Adeleke

Keyword(s):

Metabolic Pathways ◽

Drug Targets ◽

Mycoplasma Genitalium ◽

Therapeutic Drug ◽

Homologous Proteins ◽

Subtractive Genomics ◽

Cytoplasmic Proteins ◽

Novel Drug ◽

Novel Drug Targets ◽

Novel Therapeutic

Mycoplasma genitalium infection is a sexually transmitted infection that causes urethritis, cervicitis, and pelvic inflammatory disease (PID) in men and women. The global rise in antimicrobial resistance against recommended antibiotics for the treatment of M. genitalium infection has triggered the need to explore novel drug targets against this pathogen. The application of a bioinformatics approach through subtractive genomics has proven highly instrumental in predicting novel therapeutic targets against a pathogen. This study aimed to identify essential and non-homologous proteins with unique metabolic pathways in the pathogen that could serve as novel drug targets. Based on this, a manual comparison of the metabolic pathways of M. genitalium and the human host was done, generating nine pathogen-specific metabolic pathways. Additionally, the analysis of the whole proteome of M. genitalium using different bioinformatics databases generated 21 essential, non-homologous, and cytoplasmic proteins involved in nine pathogen-specific metabolic pathways. The further screening of these 21 cytoplasmic proteins in the DrugBank database generated 13 druggable proteins, which showed similarity with FDA-approved and experimental small-molecule drugs. A total of seven proteins that are involved in seven different pathogen-specific metabolic pathways were finally selected as novel putative drug targets after further analysis. Therefore, these proposed drug targets could aid in the design of potent drugs that may inhibit the functionality of these pathogen-specific metabolic pathways and, as such, lead to the eradication of this pathogen.

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Prediction of Novel Drug Targets and Vaccine Candidates against Human Lice (Insecta), Acari (Arachnida), and Their Associated Pathogens

Vaccines ◽

10.3390/vaccines10010008 ◽

2021 ◽

Vol 10 (1) ◽

pp. 8

Author(s):

Abid Ali ◽

Shabir Ahmad ◽

Pedro Machado Medeiros de Albuquerque ◽

Atif Kamil ◽

Fahdah Ayed Alshammari ◽

...

Keyword(s):

Metabolic Pathways ◽

Drug Targets ◽

Babesia Microti ◽

Economic Losses ◽

Borrelia Miyamotoi ◽

Vaccine Candidates ◽

Essential Proteins ◽

Membrane Bound ◽

Novel Drug ◽

Novel Drug Targets

The emergence of drug-resistant lice, acari, and their associated pathogens (APs) is associated with economic losses; thus, it is essential to find new appropriate therapeutic approaches. In the present study, a subtractive proteomics approach was used to predict suitable therapeutics against these vectors and their infectious agents. We found 9701 proteins in the lice (Pediculus humanus var. corporis) and acari (Ixodes scapularis, Leptotrombidium deliense), and 4822 proteins in the proteomes of their APs (Babesia microti, Borreliella mayonii, Borrelia miyamotoi, Borrelia recurrentis, Rickettsia prowazekii, Orientia tsutsugamushi str. Boryong) that were non-homologous to host proteins. Among these non-homologous proteins, 365 proteins of lice and acari, and 630 proteins of APs, were predicted as essential proteins. Twelve unique essential proteins were predicted to be involved in four unique metabolic pathways of lice and acari, and 103 unique proteins were found to be involved in 75 unique metabolic pathways of APs. The sub cellular localization analysis of 115 unique essential proteins of lice and acari and their APs revealed that 61 proteins were cytoplasmic, 42 as membrane-bound proteins and 12 proteins with multiple localization. The druggability analysis of the identified 73 cytoplasmic and multiple localization essential proteins revealed 22 druggable targets and 51 novel drug targets that participate in unique pathways of lice and acari and their APs. Further, the predicted 42 membrane bound proteins could be potential vaccine candidates. Screening of useful inhibitors against these novel targets may result in finding novel compounds efficient for the control of these parasites.

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Pathway analysis of GWAS loci identifies novel drug targets and repurposing opportunities

10.1101/425769 ◽

2018 ◽

Author(s):

Deepali Jhamb ◽

Michal Magid-Slav ◽

Mark R. Hurle ◽

Pankaj Agarwal

Keyword(s):

Drug Discovery ◽

Pathway Analysis ◽

Drug Targets ◽

Global Analysis ◽

Association Studies ◽

Genome Wide Association Studies ◽

Genome Wide ◽

If Current ◽

Novel Drug ◽

Novel Drug Targets

AbstractGenome-wide association studies (GWAS) have made considerable progress and there is emerging evidence that genetics-based targets can lead to 28% more launched drugs. However, translating the results of GWAS for drug discovery remains challenging. We analyzed 1,589 GWAS across 1,456 protein interaction pathways to translate these often, imprecise genetic loci into therapeutic hypotheses for 182 diseases. We validate these pathway-based genetic targets by testing if current drug targets are enriched in the pathway space of the same indication. Remarkably, 30% of diseases have significantly more targets in these pathways than expected by chance; the comparable number for GWAS alone (without using pathway analysis) is zero. Although pathway analysis is routine for GWAS, this study shows that the routine analysis can often enrich for drug targets, by performing a systematic global analysis to translate genetic findings into therapeutic hypotheses for new drug discovery and repositioning opportunities for current drugs.

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Combined siRNA and Small-Molecule Phenotypic Screening Identifies Targets Regulating Rhinovirus Replication in Primary Human Bronchial Epithelial Cells

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220909726 ◽

2020 ◽

Vol 25 (6) ◽

pp. 634-645 ◽

Cited By ~ 1

Author(s):

Mei Ding ◽

Christian Tyrchan ◽

Elisabeth Bäck ◽

Jörgen Östling ◽

Steffen Schubert ◽

...

Keyword(s):

Drug Discovery ◽

Small Molecule ◽

Drug Targets ◽

Phenotypic Screening ◽

Bronchial Epithelial ◽

Phenotypic Screen ◽

Tract Infections ◽

Novel Drug ◽

Novel Drug Targets

Human rhinovirus (RV) is the most common cause of acute upper respiratory tract infections and has recently been shown to play a significant role in exacerbations of asthma and chronic obstructive pulmonary disease (COPD). There is a significant unmet medical need for agents for the prevention and/or treatment of exacerbations triggered by human RV infection. Phenotypic drug discovery programs using different perturbation modalities, for example, siRNA, small-molecule compounds, and CRISPR, hold significant value for identifying novel drug targets. We have previously reported the identification of lanosterol synthase as a novel regulator of RV2 replication through a phenotypic screen of a library of siRNAs against druggable genes in normal human bronchial epithelial (NHBE) cells. Here, we describe a follow-up phenotypic screen of small-molecule compounds that are annotated to be pharmacological regulators of target genes that were identified to significantly affect RV2 replication in the siRNA primary screen of 10,500 druggable genes. Two hundred seventy small-molecule compounds selected for interacting with 122 target gene hits were screened in the primary RV2 assay in NHBE cells by quantifying viral replication via in situ hybridization followed by secondary quantitative PCR-based assays for RV2, RV14, and RV16. The described follow-up phenotypic screening allowed us to identify Fms-related tyrosine kinase 4 (FLT4) as a novel target regulating RV replication. We demonstrate that a combination of siRNA and small-molecule compound screening models is a useful phenotypic drug discovery approach for the identification of novel drug targets.

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Pangenome Analysis of Mycobacterium tuberculosis Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery

Antibiotics ◽

10.3390/antibiotics9110819 ◽

2020 ◽

Vol 9 (11) ◽

pp. 819

Author(s):

Hamza Arshad Dar ◽

Tahreem Zaheer ◽

Nimat Ullah ◽

Syeda Marriam Bakhtiar ◽

Tianyu Zhang ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Discovery ◽

Drug Targets ◽

Uridine Diphosphate ◽

Lead Compounds ◽

Diphosphate Glucose ◽

Inhibitory Potential ◽

Conserved Core ◽

Effective Drugs ◽

Novel Drug

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in M. tuberculosis broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of M. tuberculosis has provided an opportunity to explore the pangenome of the species along with the pan-phylogeny and to identify potential novel drug targets leading to drug discovery. We attempt to calculate the pangenome of M. tuberculosis that comprises a total of 150 complete genomes and performed the phylo-genomic classification and analysis. Further, the conserved core genome (1251 proteins) is subjected to various sequential filters (non-human homology, essentiality, virulence, physicochemical parameters, and pathway analysis) resulted in identification of eight putative broad-spectrum drug targets. Upon molecular docking analyses of these targets with ligands available at the DrugBank database shortlisted a total of five promising ligands with projected inhibitory potential; namely, 2′deoxy-thymidine-5′-diphospho-alpha-d-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-l-rhamnose, thymidine-5′-triphosphate, and citicoline. We are confident that with further lead optimization and experimental validation, these lead compounds may provide a sound basis to develop safe and effective drugs against tuberculosis disease in humans.

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