scholarly journals Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids

2015 ◽  
Vol 20 (5) ◽  
pp. 634-645 ◽  
Author(s):  
Marcel Kaiser ◽  
Louis Maes ◽  
Leela Pavan Tadoori ◽  
Thomas Spangenberg ◽  
Jean-Robert Ioset
Keyword(s):  
Drug Discovery ◽  
Leishmania Donovani ◽  
Human African Trypanosomiasis ◽  
Neglected Diseases ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Drug Pipeline ◽  
Malaria Box

Phenotypic screening had successfully been used for hit generation, especially in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a constant challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compounds distilled from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compounds has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addition to initiating new hit-to-lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis ( Trypanosoma brucei), Chagas disease ( Trypanosoma cruzi), and visceral leishmaniasis ( Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compounds with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed.

Current Progress on the Genomics of Schistosomiasis for Drug Discovery and Diagnostics

2020 ◽  
Vol 20 (5) ◽  
pp. 598-610
Author(s):  
Nileshkumar Meghani ◽  
Beom-Jin Lee ◽  
Hardik Amin ◽  
Behzad Nili-Ahmadabadi ◽  
Saraswathy Nagendran
Keyword(s):  
Drug Discovery ◽  
Early Stage ◽  
Diagnostic Tools ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Tremendous Progress ◽  
Significant Research ◽  
Structural Insights

For a number of decades, schistosomiasis has remained a public threat and an economic burden in a number of countries, directly impacting over 200 million people. The past 15 years have seen tremendous progress in the development of high-throughput methods for targeting or compound selection that are vital to early-stage schistosome drug discovery research. Genomewide approaches to analyze gene expression at the transcriptional and other -omic levels have helped immensely for gaining insight into the pathways and mechanisms involved in the schistosomiasis and it is expected to revolutionize the drug discovery as well as related diagnostics. This review discusses the most recent progress of pharmacology and genomics concerning schistosomiasis with a focus on drug discovery and diagnostic tools. It also provides chemical structural insights of promising targets along with available in vitro and/or in vivo data. Although significant research has been done to identify new molecules for the treatment and new methods for diagnosis, the necessity of new options for the sustainable control of schistosomiasis remains a great challenge.

scholarly journals Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

2016 ◽  
Vol 22 (6) ◽  
pp. 696-705 ◽  
Author(s):  
Tanut Kunkanjanawan ◽  
Richard Carter ◽  
Kwan-Sung Ahn ◽  
Jinjing Yang ◽  
Rangsun Parnpai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Discovery ◽  
Trinucleotide Repeat ◽  
Yeast Cells ◽  
Neural Cells ◽  
Primate Model ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Induced Pluripotent

Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients. A transgenic nonhuman primate model of HD (HD monkey) shows neuropathological, behavioral, and molecular changes similar to an HD patient. In addition, neural progenitor cells (NPCs) derived from HD monkeys can be maintained in culture and differentiated to neural cells with distinct HD cellular phenotypes including the formation of mHTT aggregates, intranuclear inclusions, and increased susceptibility to oxidative stress. Here, we evaluated the potential application of HD monkey NPCs and neural cells as an in vitro model for HD drug discovery research.

DenvInD: dengue virus inhibitors database for clinical and molecular research

2020 ◽  
Author(s):  
Vivek Dhar Dwivedi ◽  
Aditya Arya ◽  
Pardeep Yadav ◽  
Rajesh Kumar ◽  
Vinod Kumar ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Query Language ◽  
Pharmacophore Modeling ◽  
Standard Drug ◽  
Essential Information ◽  
Discovery Research ◽  
Computational Screening ◽  
Drug Discovery Research

Abstract Dengue virus (DENV) researchers often face challenges with the highly time-consuming process of collecting and curating information on known inhibitors during the standard drug discovery process. To this end, however, required collective information is not yet available on a single platform. Hence, we have developed the DenvInD database for experimentally validated DENV inhibitors against its known targets presently hosted at https://webs.iiitd.edu.in/raghava/denvind/. This database provides comprehensive information, i.e. PubChem IDs, SMILES, IC50, EC50, CC50, and wherever available Ki values of the 484 compounds in vitro validated as inhibitors against respective drug targets of DENV. Also, the DenvInD database has been linked to the user-friendly web-based interface and accessibility features, such as simple search, advanced search and data browsing. All the required data curation was conducted manually from the reported scientific literature and PubChem. The collected information was then organized into the DenvInD database using sequence query language under user interface by hypertext markup language. DenvInD is the first useful repository of its kind which would augment the DENV drug discovery research by providing essential information on known DENV inhibitors for molecular docking, computational screening, pharmacophore modeling and quantitative structure-activity relationship modeling.

scholarly journals In Vitro and In Vivo Antitrypanosomal Activities of Methanol Extract of Echinops kebericho Roots

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Debela Abdeta ◽  
Nigatu Kebede ◽  
Mirutse Giday ◽  
Getachew Terefe ◽  
Solomon Mequanente Abay
Keyword(s):  
Body Weight ◽  
Neglected Tropical Diseases ◽  
Field Isolate ◽  
Parasite Load ◽  
Phytochemical Analysis ◽  
Isolation And Purification ◽  
Discovery Research ◽  
Drug Discovery Research

Microbial resistance to the few conventional antitrypanosomal drugs, increasing resistance of vectors to insecticides, lack of effective vaccines, and adverse effects of the existing antitrypanosomal drugs justify the urgent need for effective, tolerable, and affordable drugs. We assessed antitrypanosomal effects of the hydromethanolic extract of Echinops kebericho Mesfin roots against Trypanosoma congolense field isolate using in vitro and in vivo techniques. Parasite load, packed cell volume (PCV), body weight, and rectal temperature in Swiss albino mice were assessed. This finding is part of the outcomes of drug discovery research for neglected tropical diseases. The extract arrested the motility of trypanosomes within 40 min at 4 and 2 mg/mL concentration, whereas in the untreated control, motility continued for more than 160 min. The extract also reduced parasitemia and prevented drop in PCV and body weight significantly (p<0.05), as compared to control. Phytochemical analysis showed the presence of flavonoids, triterpenes, steroids, saponins, glycosides, tannins, and alkaloids. It is observed that this extract has activity against the parasite. Isolation and purification of specific compounds are required to identify hit compounds responsible for the antitrypanosomal activity of the studied medicinal plant.

scholarly journals Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

2013 ◽  
Vol 18 (10) ◽  
pp. 1234-1245 ◽  
Author(s):  
Ashley Wolfe ◽  
Belinda O’Clair ◽  
Vincent E. Groppi ◽  
Dyke P. McEwen
Keyword(s):  
Growth Factor ◽  
Umbilical Vein ◽  
Dermal Fibroblasts ◽  
Tube Length ◽  
Endothelial Cell Proliferation ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Angiogenesis Model

Angiogenesis, the formation of new vessels from preexisting vessels, involves multiple cell types acting in concert to cause endothelial cell proliferation, migration, and differentiation into microvascular arrays. Under pathologic conditions, microenvironment changes result in altered blood vessel production. Historically, in vitro angiogenesis assays study individual aspects of the process and tend to be variable, difficult to quantify, and limited in clinical relevance. Here, we describe a kinetic, quantitative, co-culture angiogenesis model and demonstrate its relevance to in vivo pharmacology. Similar to in vivo angiogenesis, a co-culture of human umbilical vein endothelial cells with normal human dermal fibroblasts remains sensitive to multiple cytokines, resulting in a concentration-dependent stimulation of tube formation over time. Treatment with axitinib, a selective vascular endothelial growth factor (VEGF) antagonist, inhibited VEGF-mediated tube length and branch point formation and was selective for inhibiting VEGF over basic fibroblast growth factor (bFGF), similar to previous studies. Conversely, an FGFR-1 selective compound, PD-161570, was more potent at inhibiting bFGF-mediated angiogenesis. These results demonstrate the cytokine dynamics, selective pharmacology, and translational application of this model system. Finally, combining quantitative angiogenic biology with kinetic, live-content imaging highlights the importance of using validated in vitro models in drug discovery research.

scholarly journals In Vitro Susceptibilities of Leishmania donovani Promastigote and Amastigote Stages to Antileishmanial Reference Drugs: Practical Relevance of Stage-Specific Differences

2009 ◽  
Vol 53 (9) ◽  
pp. 3855-3859 ◽  
Author(s):  
Marieke Vermeersch ◽  
Raquel Inocêncio da Luz ◽  
Kim Toté ◽  
Jean-Pierre Timmermans ◽  
Paul Cos ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Leishmania Donovani ◽  
Crystalline Substance ◽  
Sodium Stibogluconate ◽  
Cellular Mechanisms ◽  
Intracellular Amastigotes ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Primary Mouse

ABSTRACT The in vitro susceptibilities of the reference strain Leishmania donovani MHOM/ET/67/L82 to sodium stibogluconate, amphotericin B, miltefosine, and the experimental compound PX-6518 were determined for extracellular log-phase promastigotes, established axenic amastigotes, fresh spleen-derived amastigotes, and intracellular amastigotes in primary mouse peritoneal macrophages. Susceptibility to amphotericin B did not differ across the various axenic models (50% inhibitory concentrations [IC50], 0.6 to 0.7 μM), and amphotericin B showed slightly higher potency against intracellular amastigotes (IC50, 0.1 to 0.4 μM). A similar trend was observed for miltefosine, with comparable efficacies against the extracellular (IC50, 0.4 to 3.8 μM) and intracellular (IC50, 0.9 to 4.3 μM) stages. Sodium stibogluconate, used either as Pentostam or as a crystalline substance, was inactive against all axenic stages (IC50, >64 μg SbV/ml) but showed good efficacy against intracellular amastigotes (IC50, 22 to 28 μg SbV/ml); the crystalline substance was about two to three times more potent (IC50, 9 to 11 μg SbV/ml). The activity profile of PX-6518 was comparable to that of sodium stibogluconate, but at a much higher potency (IC50, 0.1 μg/ml). In conclusion, the differential susceptibility determines which in vitro models are appropriate for either drug screening or resistance monitoring of clinical field isolates. Despite the more complex and labor-intensive protocol, the current results support the intracellular amastigote model as the gold standard for in vitro Leishmania drug discovery research and for evaluation of the resistance of field strains, since it also includes host cell-mediated effects. Axenic systems can be recommended only for compounds for which no cellular mechanisms are involved, for example, amphotericin B and miltefosine.

scholarly journals In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Parasitology ◽  
2017 ◽  
Vol 144 (13) ◽  
pp. 1783-1790 ◽  
Author(s):  
ALVARO MARTIN-MONTES ◽  
MERY SANTIVAÑEZ-VELIZ ◽  
ELSA MORENO-VIGURI ◽  
RUBÉN MARTÍN-ESCOLANO ◽  
CARMEN JIMÉNEZ-MONTES ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Leishmania Donovani ◽  
Mannich Base ◽  
Neglected Diseases ◽  
Leishmania Braziliensis ◽  
Reference Drug ◽  
Iron Superoxide Dismutase ◽  
Therapeutic Tools

SUMMARYLeishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

scholarly journals Preparation of Three-dimensional (3-D) Human Liver (HepaRG) Cultures for Histochemical and Immunohistochemical Staining and Light Microscopic Evaluation

2018 ◽  
Vol 46 (6) ◽  
pp. 653-659 ◽  
Author(s):  
Natasha P. Clayton ◽  
Alanna Burwell ◽  
Heather Jensen ◽  
Barbara F. Williams ◽  
Quashana D. Brown ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Human Liver ◽  
Three Dimensional ◽  
Culture Systems ◽  
Discovery Research ◽  
Glass Slides ◽  
Drug Discovery Research ◽  
Microscopic Evaluation

The use of three-dimensional (3-D) in vitro culture systems (spheroids, organoids) in biomolecular and drug discovery research has become increasingly popular. The popularity is due, in part, to a diminished reliance on animal bioassays and a desire to develop physiologically relevant cell culture systems that simulate the in vivo tissue microenvironment. Most evaluations of 3-D cultures are by confocal microscopy and high-content imaging; however, these technologies do not allow for detailed cellular morphologic assessments or permit basic hematoxylin and eosin histologic evaluations. There are few studies that have reported detailed processes for preparing 3-D cultures for paraffin embedding and subsequent use for histochemical or immunohistochemical staining. In an attempt to do so, we have developed a protocol to paraffin-embed human liver spheroids that can be sectioned with a microtome and mounted onto glass slides for routine histochemical and immunohistochemical staining and light microscopic evaluations.

scholarly journals Chemical toxicity prediction based on semi-supervised learning and graph convolutional neural network

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jiarui Chen ◽  
Yain-Whar Si ◽  
Chon-Wai Un ◽  
Shirley W. I. Siu
Keyword(s):  
Neural Network ◽  
Supervised Learning ◽  
Superior Performance ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Toxicity Prediction ◽  
Discovery Research ◽  
Drug Discovery Research

AbstractAs safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases. Our optimal model SSL-GCN is hosted on an online server accessible through: https://app.cbbio.online/ssl-gcn/home.

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