Innovation in bioanalytical strategies and in vitro drug–drug interaction study approaches in drug discovery

Bioanalysis ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 513-532
Author(s):  
Saraswathisreeram Pranush Kumar ◽  
Deeki Doma Sherpa ◽  
Amit Kumar Sahu ◽  
Tarang Jadav ◽  
Rakesh Kumar Tekade ◽  
...  
Keyword(s):  
Drug Discovery ◽  
3D Cell Culture ◽  
Full Potential ◽  
High Throughput Analysis ◽  
Discovery Research ◽  
Sandwich Culture ◽  
Conventional Drug ◽  
Drug Discovery Research ◽  
Bioanalytical Techniques

Failure to evaluate actual toxicities of investigational molecules in drug discovery is majorly due to inadequate evaluation of their pharmacokinetics. Limitation of conventional drug metabolism profiling procedure demands advancement of existing approaches. Various techniques such as 3D cell culture system, bio microfluidic OoC model, sandwich culture model is in pipeline to be employed at their full potential in drug discovery phase. Although they outweigh the conventional techniques in various aspects, a more detailed exploration of applicability in terms of automation and high throughput analysis is required. This review extensively discusses various ongoing innovations in bioanalytical techniques. The review also proposed various scientific strategies to be adopted for prior assessment of interaction possibilities in translational drug discovery research.

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.

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 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.

scholarly journals Drug metabolism activity is a Critical Intrinsic Selector for Hepatocytes to elongate cell lifespan by using a cell-killing antibiotic

2021 ◽  
Author(s):  
Saeko Akiyama ◽  
Noriaki Saku ◽  
Shoko Miyata ◽  
Kenta Ite ◽  
Masashi Toyoda ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Culture System ◽  
Hepatic Function ◽  
Human Hepatocytes ◽  
Hepatocyte Proliferation ◽  
Pharmacokinetic Studies ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Fetal Fibroblasts

ABSTRACTThe liver plays many important roles in homeostasis, including drug detoxification, metabolism, and bile production. Hepatocytes, which are the main constituent cells of the liver, play an important role in the pathogenesis of liver diseases, identification of candidate compounds in drug discovery research, pharmacokinetic studies, and toxicity evaluation. Human hepatocytes are, however, difficult to grow in normal in vitro culture systems, making it difficult to secure cell numbers. As an alternative, evaluation systems using animal models and hepatocellular carcinoma cells have been established, but interspecies and interracial differences and low hepatic function have been pointed out as problems. Therefore, there is still a need for a highly stable method to prepare human hepatocytes with sufficient functionality. In this study, we aimed to establish an in vitro long-term culture system that enables stable proliferation and maintenance of the functionality of human hepatocytes to stably supply human hepatocytes. In the established culture system, the stable proliferation of human hepatocytes was achieved by co-culturing hepatocytes with mouse fetal fibroblasts to dedifferentiate them into hepatic progenitor-like cells. Furthermore, we succeeded in purifying human hepatocytes by puromycin with a rapid cytocidal effect and proliferating them to over 30 population doublings for more than 200 days. Hepatocytes with high expression of cytochrome P450 genes survived after exposure to cytotoxic antibiotics because of enhanced drug-metabolizing activity. These results show that the above culture system enables simple and efficient hepatocyte proliferation, and is considered to be an effective method for stable supply of hepatocytes and significant cost reduction in drug discovery research.

scholarly journals Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 349
Author(s):  
Asim Najmi ◽  
Sadique A. Javed ◽  
Mohammed Al Bratty ◽  
Hassan A. Alhazmi
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Therapeutic Agents ◽  
Throughput Capacity ◽  
Scientific Interest ◽  
Comprehensive Overview ◽  
Natural Sources ◽  
Discovery Research ◽  
Drug Discovery Research

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.

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