scholarly journals Challenges in Drug Discovery against Tuberculosis

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.

scholarly journals Machine Learning Methods in Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5277
Author(s):  
Lauv Patel ◽  
Tripti Shukla ◽  
Xiuzhen Huang ◽  
David W. Ussery ◽  
Shanzhi Wang
Keyword(s):  
Machine Learning ◽  
Deep Learning ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Learning Algorithms ◽  
Machine Learning Techniques ◽  
Online Information ◽  
Drug Candidates ◽  
Novel Drug

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.

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

Biomedicines ◽  
2016 ◽  
Vol 4 (4) ◽  
pp. 27 ◽  
Author(s):  
Suhas Vasaikar ◽  
Pooja Bhatia ◽  
Partap Bhatia ◽  
Koon Chu Yaiw
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 722 ◽  
Author(s):  
Arijit Bhattacharya ◽  
Audrey Corbeil ◽  
Rubens L. do Monte-Neto ◽  
Christopher Fernandez-Prada
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Brucei ◽  
Leishmania Species ◽  
Lead Compounds ◽  
Technological Advances ◽  
Compound Screening ◽  
Trypanosomatid Parasites ◽  
Novel Drug

Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds.

scholarly journals Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

2019 ◽  
Vol 5 (5) ◽  
pp. eaau9093 ◽  
Author(s):  
Santiago G. Lago ◽  
Jakub Tomasik ◽  
Geertje F. van Rees ◽  
Hannah Steeb ◽  
David A. Cox ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Single Cell ◽  
Drug Targets ◽  
Ex Vivo ◽  
Signaling Network ◽  
Antipsychotic Treatment ◽  
Channel Blockers ◽  
Functional Responses ◽  
Novel Approach

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3β) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1–calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

scholarly journals Bioinformatics in translational drug discovery

2017 ◽  
Vol 37 (4) ◽  
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.

Molecular context of ADP-ribosylation in schistosomes for drug discovery and vaccine development

2020 ◽  
Vol 17 ◽  
Author(s):  
Amandla Chutshela ◽  
Priscilla Masamba ◽  
Babatunji Emmanuel Oyinloye ◽  
Abidemi Paul Kappo
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Vaccine Development ◽  
Neglected Tropical Diseases ◽  
Adenosine Diphosphate ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Molecular Context ◽  
Living Organisms

: Schistosome infection is regarded as one of the most important and neglected tropical diseases associated with poor sanitation. Like other living organisms, schistosomes employ multiple biological processes, of which some are regulated by a post-translational modification called Adenosine diphosphate-ribosylation (ADP-ribosylation), catalyzed by ADPribosyltransferases. ADP-ribosylation is the addition of ADP-ribose moieties from nicotinamide adenine dinucleotide (NAD+) to various targets, which include proteins and nucleotides. It is crucial in biological processes such as DNA repair, apoptosis, carbohydrate metabolism and catabolism. In the absence of a vaccine against schistosomiasis, this becomes a promising pathway in the identification of drug targets against various forms of this infection. The tegument of the worm is an encouraging immunogenic target for anti-schistosomal vaccine development. Vaccinology, molecular modeling and target-based drug discovery strategies have been used for years in drug discovery and for vaccine development. In this paper, we outline ADP-ribosylation and other different approaches to drug discovery and vaccine development against schistosomiasis.

scholarly journals Establishment of a stable transfection method in Babesia microti and identification of a novel bidirectional promoter of Babesia microti

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dabbu Kumar Jaijyan ◽  
Kavitha Govindasamy ◽  
Jyoti Singh ◽  
Shreya Bhattacharya ◽  
Agam Prasad Singh
Keyword(s):  
Drug Targets ◽  
Reverse Genetics ◽  
Developmental Stages ◽  
Vaccine Development ◽  
Genetic Manipulation ◽  
Babesia Microti ◽  
Stable Transfection ◽  
Growth Curve Analysis ◽  
Transfection Method

Abstract Babesia microti, an emerging human pathogen, is primarily transmitted through a bite of an infected tick and blood transfusions in human. Stable transfection technique has been reported in many protozoan parasites over the past few years. However, in vivo transient and stable transfection method has not been established for Babesia microti. Here, for the first time, we present a method of transient as well as stable transfection of the Babesia microti (B. microti) in the in vivo conditions. We have identified a novel promoter of B. microti. We also demonstrated that Plasmodium berghei DHFR promoter is recognized and functional in B. microti. We show that BM-CTQ41297 promoter control the expression of two genes, which are present on either side and thus represents a bi-functional promoter in B. microti. The predicted promoter activity values using Promoter 2.0 program is higher for BM- CTQ41297 promoter than strong promoters such as β-actin, ef-1β, and many other promoters. Furthermore, we discovered a non-essential locus for the genetic manipulation of the parasite, allowing us to stably integrate foreign genes; GFP, mCherry, into the B. microti. The transfection using an electroporation method and genetic manipulation of B. microti is now achievable and it is possible to obtain transfected viable parasites under in vivo growing conditions. The growth curve analysis of transfected and WT B. microti are similar indicating no defects in the transgenic parasites. This study will enable other researchers in understanding the B. microti biology, host modulation and diverse parasite developmental stages using reverse genetics and holds great potential to identify novel drug targets and vaccine development.

scholarly journals Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 641
Author(s):  
Elisa Rampacci ◽  
Valentina Stefanetti ◽  
Fabrizio Passamonti ◽  
Marcela Henao-Tamayo
Keyword(s):  
Drug Discovery ◽  
Vaccine Development ◽  
Nontuberculous Mycobacteria ◽  
Critical Role ◽  
Developed Countries ◽  
Alternative Methods ◽  
In Vivo Models ◽  
Early Drug

Nontuberculous mycobacteria (NTM) represent an increasingly prevalent etiology of soft tissue infections in animals and humans. NTM are widely distributed in the environment and while, for the most part, they behave as saprophytic organisms, in certain situations, they can be pathogenic, so much so that the incidence of NTM infections has surpassed that of Mycobacterium tuberculosis in developed countries. As a result, a growing body of the literature has focused attention on the critical role that drug susceptibility tests and infection models play in the design of appropriate therapeutic strategies against NTM diseases. This paper is an overview of the in vitro and in vivo models of NTM infection employed in the preclinical phase for early drug discovery and vaccine development. It summarizes alternative methods, not fully explored, for the characterization of anti-mycobacterial compounds.

scholarly journals Exosomes: Versatile Nano Mediators of Immune Regulation

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1557 ◽  
Author(s):  
Li ◽  
Wang ◽  
Peng ◽  
Huyan ◽  
Cacalano
Keyword(s):  
Cellular Differentiation ◽  
Vaccine Development ◽  
Cell Communication ◽  
Diagnostic Tools ◽  
Biological Processes ◽  
Pathological Conditions ◽  
Wide Range ◽  
Almost All ◽  
Novel Drug

One of many types of extracellular vesicles (EVs), exosomes are nanovesicle structures that are released by almost all living cells that can perform a wide range of critical biological functions. Exosomes play important roles in both normal and pathological conditions by regulating cell-cell communication in cancer, angiogenesis, cellular differentiation, osteogenesis, and inflammation. Exosomes are stable in vivo and they can regulate biological processes by transferring lipids, proteins, nucleic acids, and even entire signaling pathways through the circulation to cells at distal sites. Recent advances in the identification, production, and purification of exosomes have created opportunities to exploit these structures as novel drug delivery systems, modulators of cell signaling, mediators of antigen presentation, as well as biological targeting agents and diagnostic tools in cancer therapy. This review will examine the functions of immunocyte-derived exosomes and their roles in the immune response under physiological and pathological conditions. The use of immunocyte exosomes in immunotherapy and vaccine development is discussed.

scholarly journals Kinomics platform using GBM tissue identifies BTK as being associated with higher patient survival

2021 ◽  
Vol 4 (12) ◽  
pp. e202101054
Author(s):  
Sofian Al Shboul ◽  
Olimpia E Curran ◽  
Javier A Alfaro ◽  
Fiona Lickiss ◽  
Erisa Nita ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Patient Survival ◽  
Specific Activity ◽  
Ex Vivo ◽  
Culture Models ◽  
Novel Drug ◽  
Btk Inhibitors ◽  
Novel Drug Targets

Better understanding of GBM signalling networks in-vivo would help develop more physiologically relevant ex vivo models to support therapeutic discovery. A “functional proteomics” screen was undertaken to measure the specific activity of a set of protein kinases in a two-step cell-free biochemical assay to define dominant kinase activities to identify potentially novel drug targets that may have been overlooked in studies interrogating GBM-derived cell lines. A dominant kinase activity derived from the tumour tissue, but not patient-derived GBM stem-like cell lines, was Bruton tyrosine kinase (BTK). We demonstrate that BTK is expressed in more than one cell type within GBM tissue; SOX2-positive cells, CD163-positive cells, CD68-positive cells, and an unidentified cell population which is SOX2-negative CD163-negative and/or CD68-negative. The data provide a strategy to better mimic GBM tissue ex vivo by reconstituting more physiologically heterogeneous cell co-culture models including BTK-positive/negative cancer and immune cells. These data also have implications for the design and/or interpretation of emerging clinical trials using BTK inhibitors because BTK expression within GBM tissue was linked to longer patient survival.

Sign in / Sign up

Export Citation Format

Share Document