scholarly journals DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences

2018 ◽  
Vol 399 (7) ◽  
pp. 691-710 ◽  
Author(s):  
Verena Kunig ◽  
Marco Potowski ◽  
Anne Gohla ◽  
Andreas Brunschweiger
Keyword(s):  
Bioactive Compounds ◽  
Small Molecule ◽  
Dna Sequences ◽  
Large Scale ◽  
Biomedical Sciences ◽  
Target Proteins ◽  
Protein Ligands ◽  
Compound Libraries ◽  
Allosteric Binding Sites ◽  
Selection Of

Abstract DNA-encoded compound libraries are a highly attractive technology for the discovery of small molecule protein ligands. These compound collections consist of small molecules covalently connected to individual DNA sequences carrying readable information about the compound structure. DNA-tagging allows for efficient synthesis, handling and interrogation of vast numbers of chemically synthesized, drug-like compounds. They are screened on proteins by an efficient, generic assay based on Darwinian principles of selection. To date, selection of DNA-encoded libraries allowed for the identification of numerous bioactive compounds. Some of these compounds uncovered hitherto unknown allosteric binding sites on target proteins; several compounds proved their value as chemical biology probes unraveling complex biology; and the first examples of clinical candidates that trace their ancestry to a DNA-encoded library were reported. Thus, DNA-encoded libraries proved their value for the biomedical sciences as a generic technology for the identification of bioactive drug-like molecules numerous times. However, large scale experiments showed that even the selection of billions of compounds failed to deliver bioactive compounds for the majority of proteins in an unbiased panel of target proteins. This raises the question of compound library design.

scholarly journals BonMOLière: Small-Sized Libraries of Readily Purchasable Compounds, Optimized to Produce Genuine Hits in Biological Screens across the Protein Space

2021 ◽  
Vol 22 (15) ◽  
pp. 7773
Author(s):  
Neann Mathai ◽  
Conrad Stork ◽  
Johannes Kirchmair
Keyword(s):  
Large Scale ◽  
Computational Approach ◽  
Large Sets ◽  
Compound Libraries ◽  
Wide Range ◽  
Protein Space ◽  
High Chance ◽  
Large Scale Screening ◽  
Early Drug ◽  
Selection Of

Experimental screening of large sets of compounds against macromolecular targets is a key strategy to identify novel bioactivities. However, large-scale screening requires substantial experimental resources and is time-consuming and challenging. Therefore, small to medium-sized compound libraries with a high chance of producing genuine hits on an arbitrary protein of interest would be of great value to fields related to early drug discovery, in particular biochemical and cell research. Here, we present a computational approach that incorporates drug-likeness, predicted bioactivities, biological space coverage, and target novelty, to generate optimized compound libraries with maximized chances of producing genuine hits for a wide range of proteins. The computational approach evaluates drug-likeness with a set of established rules, predicts bioactivities with a validated, similarity-based approach, and optimizes the composition of small sets of compounds towards maximum target coverage and novelty. We found that, in comparison to the random selection of compounds for a library, our approach generates substantially improved compound sets. Quantified as the “fitness” of compound libraries, the calculated improvements ranged from +60% (for a library of 15,000 compounds) to +184% (for a library of 1000 compounds). The best of the optimized compound libraries prepared in this work are available for download as a dataset bundle (“BonMOLière”).

scholarly journals Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

2019 ◽  
Vol 10 (45) ◽  
pp. 10481-10492 ◽  
Author(s):  
Marco Potowski ◽  
Florian Losch ◽  
Elena Wünnemann ◽  
Janina K. Dahmen ◽  
Silvia Chines ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dna Sequences ◽  
Solid Phase ◽  
Alder Reaction ◽  
Solid Support ◽  
Diels Alder ◽  
Dna Oligonucleotides ◽  
Compound Libraries ◽  
Diels Alder Reaction ◽  
Selection Of

DNA-encoded compound libraries are widely used in drug discovery. Screening of catalysts for compatibility with solid phase-coupled DNA sequences guided the selection of encoded reactions, exemplified by a Zn(II)-mediated aza-Diels–Alder reaction.

Platelet Anti-Aggregating Activity and Tolerance of Clopidogrel in Atherosclerotic Patients

1996 ◽  
Vol 76 (06) ◽  
pp. 0939-0943 ◽  
Author(s):  
B Boneu ◽  
G Destelle ◽  
Keyword(s):  
Platelet Aggregation ◽  
Large Scale ◽  
Bleeding Time ◽  
Antithrombotic Activity ◽  
Ambulatory Patients ◽  
Patients At Risk ◽  
Set Up ◽  
Ischemic Events ◽  
Large Scale Clinical Trial ◽  
Selection Of

SummaryThe anti-aggregating activity of five rising doses of clopidogrel has been compared to that of ticlopidine in atherosclerotic patients. The aim of this study was to determine the dose of clopidogrel which should be tested in a large scale clinical trial of secondary prevention of ischemic events in patients suffering from vascular manifestations of atherosclerosis [CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial]. A multicenter study involving 9 haematological laboratories and 29 clinical centers was set up. One hundred and fifty ambulatory patients were randomized into one of the seven following groups: clopidogrel at doses of 10, 25, 50,75 or 100 mg OD, ticlopidine 250 mg BID or placebo. ADP and collagen-induced platelet aggregation tests were performed before starting treatment and after 7 and 28 days. Bleeding time was performed on days 0 and 28. Patients were seen on days 0, 7 and 28 to check the clinical and biological tolerability of the treatment. Clopidogrel exerted a dose-related inhibition of ADP-induced platelet aggregation and bleeding time prolongation. In the presence of ADP (5 \lM) this inhibition ranged between 29% and 44% in comparison to pretreatment values. The bleeding times were prolonged by 1.5 to 1.7 times. These effects were non significantly different from those produced by ticlopidine. The clinical tolerability was good or fair in 97.5% of the patients. No haematological adverse events were recorded. These results allowed the selection of 75 mg once a day to evaluate and compare the antithrombotic activity of clopidogrel to that of aspirin in the CAPRIE trial.

scholarly journals Rapid, large-scale species discovery in hyperdiverse taxa using 1D MinION sequencing

BMC Biology ◽  
2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Amrita Srivathsan ◽  
Emily Hartop ◽  
Jayanthi Puniamoorthy ◽  
Wan Ting Lee ◽  
Sujatha Narayanan Kutty ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Large Scale ◽  
Low Cost ◽  
Small Body ◽  
Small Subset ◽  
Similar Species ◽  
Large Species ◽  
Morphological Examination ◽  
Species Discovery ◽  
Short Period

Abstract Background More than 80% of all animal species remain unknown to science. Most of these species live in the tropics and belong to animal taxa that combine small body size with high specimen abundance and large species richness. For such clades, using morphology for species discovery is slow because large numbers of specimens must be sorted based on detailed microscopic investigations. Fortunately, species discovery could be greatly accelerated if DNA sequences could be used for sorting specimens to species. Morphological verification of such “molecular operational taxonomic units” (mOTUs) could then be based on dissection of a small subset of specimens. However, this approach requires cost-effective and low-tech DNA barcoding techniques because well-equipped, well-funded molecular laboratories are not readily available in many biodiverse countries. Results We here document how MinION sequencing can be used for large-scale species discovery in a specimen- and species-rich taxon like the hyperdiverse fly family Phoridae (Diptera). We sequenced 7059 specimens collected in a single Malaise trap in Kibale National Park, Uganda, over the short period of 8 weeks. We discovered > 650 species which exceeds the number of phorid species currently described for the entire Afrotropical region. The barcodes were obtained using an improved low-cost MinION pipeline that increased the barcoding capacity sevenfold from 500 to 3500 barcodes per flowcell. This was achieved by adopting 1D sequencing, resequencing weak amplicons on a used flowcell, and improving demultiplexing. Comparison with Illumina data revealed that the MinION barcodes were very accurate (99.99% accuracy, 0.46% Ns) and thus yielded very similar species units (match ratio 0.991). Morphological examination of 100 mOTUs also confirmed good congruence with morphology (93% of mOTUs; > 99% of specimens) and revealed that 90% of the putative species belong to the neglected, megadiverse genus Megaselia. We demonstrate for one Megaselia species how the molecular data can guide the description of a new species (Megaselia sepsioides sp. nov.). Conclusions We document that one field site in Africa can be home to an estimated 1000 species of phorids and speculate that the Afrotropical diversity could exceed 200,000 species. We furthermore conclude that low-cost MinION sequencers are very suitable for reliable, rapid, and large-scale species discovery in hyperdiverse taxa. MinION sequencing could quickly reveal the extent of the unknown diversity and is especially suitable for biodiverse countries with limited access to capital-intensive sequencing facilities.

scholarly journals Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications

Marine Drugs ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. 241
Author(s):  
Shaden A. M. Khalifa ◽  
Eslam S. Shedid ◽  
Essa M. Saied ◽  
Amir Reza Jassbi ◽  
Fatemeh H. Jamebozorgi ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Biomedical Applications ◽  
Large Scale ◽  
Biological Activities ◽  
Scale Production ◽  
Pharmacological Activities ◽  
Large Scale Production ◽  
Marine Products ◽  
Hiv 1 ◽  
Successful Phase

Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.

scholarly journals Methodology for Determining the Location of River Ports on a Modernized Waterway Based on Non-Cost Criteria: A Case Study of the Odra River Waterway

2021 ◽  
Vol 13 (6) ◽  
pp. 3571
Author(s):  
Bogusz Wiśnicki ◽  
Dorota Dybkowska-Stefek ◽  
Justyna Relisko-Rybak ◽  
Łukasz Kolanda
Keyword(s):  
Large Scale ◽  
Multicriteria Decision Making ◽  
Research Process ◽  
Optimal Selection ◽  
Investment Projects ◽  
Odra River ◽  
Research Problems ◽  
Selection Of ◽  
Construction Works

The paper responds to research problems related to the implementation of large-scale investment projects in waterways in Europe. As part of design and construction works, it is necessary to indicate river ports that play a major role within the European transport network as intermodal nodes. This entails a number of challenges, the cardinal one being the optimal selection of port locations, taking into account the new transport, economic, and geopolitical situation that will be brought about by modernized waterways. The aim of the paper was to present an original methodology for determining port locations for modernized waterways based on non-cost criteria, as an extended multicriteria decision-making method (MCDM) and employing GIS (Geographic Information System)-based tools for spatial analysis. The methodology was designed to be applicable to the varying conditions of a river’s hydroengineering structures (free-flowing river, canalized river, and canals) and adjustable to the requirements posed by intermodal supply chains. The method was applied to study the Odra River Waterway, which allowed the formulation of recommendations regarding the application of the method in the case of different river sections at every stage of the research process.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

scholarly journals Predicting Shifts in Land Suitability for Maize Cultivation Worldwide Due to Climate Change: A Modeling Approach

Land ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 295
Author(s):  
Yuan Gao ◽  
Anyu Zhang ◽  
Yaojie Yue ◽  
Jing’ai Wang ◽  
Peng Su
Keyword(s):  
Climate Change ◽  
Crop Production ◽  
Large Scale ◽  
Land Suitability ◽  
Large Scale Assessment ◽  
Scale Assessment ◽  
Maize Cultivation ◽  
Large Scale Screening ◽  
Selection Of

Suitable land is an important prerequisite for crop cultivation and, given the prospect of climate change, it is essential to assess such suitability to minimize crop production risks and to ensure food security. Although a variety of methods to assess the suitability are available, a comprehensive, objective, and large-scale screening of environmental variables that influence the results—and therefore their accuracy—of these methods has rarely been explored. An approach to the selection of such variables is proposed and the criteria established for large-scale assessment of land, based on big data, for its suitability to maize (Zea mays L.) cultivation as a case study. The predicted suitability matched the past distribution of maize with an overall accuracy of 79% and a Kappa coefficient of 0.72. The land suitability for maize is likely to decrease markedly at low latitudes and even at mid latitudes. The total area suitable for maize globally and in most major maize-producing countries will decrease, the decrease being particularly steep in those regions optimally suited for maize at present. Compared with earlier research, the method proposed in the present paper is simple yet objective, comprehensive, and reliable for large-scale assessment. The findings of the study highlight the necessity of adopting relevant strategies to cope with the adverse impacts of climate change.

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