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 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.

scholarly journals Joint epitope selection and spacer design for string-of-beads vaccines

2020 ◽  
Author(s):  
Emilio Dorigatti ◽  
Benjamin Schubert
Keyword(s):  
Antigen Processing ◽  
State Of The Art ◽  
Computational Approach ◽  
Population Coverage ◽  
Current State ◽  
Fixed Set ◽  
Epitope Selection ◽  
High Chance ◽  
Selection Of ◽  
Design Steps

AbstractMotivationConceptually, epitope-based vaccine design poses two distinct problems: (1) selecting the best epitopes eliciting the strongest possible immune response, and (2) arranging and linking the selected epitopes through short spacer sequences to string-of-beads vaccines so as to increase the recovery likelihood of each epitope during antigen processing. Current state-of-the-art approaches solve this design problem sequentially. Consequently, such approaches are unable to capture the inter-dependencies between the two design steps, usually emphasizing theoretical immunogenicity over correct vaccine processing and resulting in vaccines with less effective immunogencity.ResultsIn this work, we present a computational approach based on linear programming that solves both design steps simultaneously, allowing to weigh the selection of a set of epitopes that have great immunogenic potential against their assembly into a string-of-beads construct that provides a high chance of recovery. We conducted Monte-Carlo cleavage simulations to show that, indeed, a fixed set of epitopes often cannot be assembled adequately, whereas selecting epitopes to accommodate proper cleavage requirements substantially improves their recovery probability and thus the effective immunogenicity, pathogen, and population coverage of the resulting vaccines by at least two fold.AvailabilityThe software and the data analyzed are available at https://github.com/SchubertLab/JessEV

scholarly journals Hotspot Hunter: a computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes

2008 ◽  
Vol 9 (S1) ◽  
Author(s):  
Guang Lan Zhang ◽  
Asif M Khan ◽  
Kellathur N Srinivasan ◽  
AT Heiny ◽  
KX Lee ◽  
...  
Keyword(s):  
Large Scale ◽  
Computational System ◽  
Large Scale Screening ◽  
Selection Of

Large Scale Screening Programme for Selection of Antisera for Radioimmunoassay of Human Parathyroid Hormone

1983 ◽  
Vol 4 (2) ◽  
pp. 175-206 ◽  
Author(s):  
Joan M. Zanelli ◽  
B. Rafferty ◽  
B. Apostolou ◽  
G. Court ◽  
B. A. L. Hurn
Keyword(s):  
Parathyroid Hormone ◽  
Large Scale ◽  
Screening Programme ◽  
Human Parathyroid Hormone ◽  
Large Scale Screening ◽  
Selection Of

scholarly journals Geochemistry of iron in soils of Vojvodina, Sumadija and Northern Pomoravlje

2002 ◽  
pp. 17-28 ◽  
Author(s):  
Nikola Kostic ◽  
Adam Dangic ◽  
Miodrag Jakovljevic
Keyword(s):  
Iron Content ◽  
Large Scale ◽  
Total Iron ◽  
Sample Collection ◽  
Site Location ◽  
Average Value ◽  
Mn Oxide ◽  
Wide Range ◽  
Parent Rocks ◽  
Selection Of

Iron is one of the most common elements in the Earth's crust and it is fourth on the list of abundance after oxygen, silicon and aluminum. It plays an important role in the biosphere. In plants it is necessary for the formation of chlorophyll, while in animals it acts in transferring oxygen from air or water to animal tissue. During a large-scale sample collection a regular orthogonal 10x10 km grid has been used to avoid bias in site location. From the set of about 3000 samples from Vojvodina, Sumadija and Northern Pomoravlje, a selection of samples (from the arable layer 0-25 cm) has been taken to represent the most important soil types. Total iron content has been determined by the atomic absorption spectrophotometric method (AAS). The soil samples have also been assayed for metal on a phase-specific basis following procedures according to the EC protocol Spatial distribution of iron content over the investigated area has been presented in a pedogeochemical map. The presented results have shown a wide range of iron contents, from 0.73 to 10.86% Fe. Statistical analysis of the results obtained from 103 samples has shown an average value of 4.06% Fe with the standard deviation of 1.682 and the coefficient of variation of 41.49%. Iron contents lower than 2.10% have been found in 4.32% of the samples, medium and average values (2.10-4.97% Fe) have been found in 55% of the samples, values higher then the average have been found in 26.3% of the samples and the contents higher than 7.86% have been found in 13.96% of the samples. Arenosols and rigosols developed on aeolian sands have shown the lowest levels of total iron, from 0.73 to 1.82% Fe. On the other side ranker developed on serpentinite has shown maximum contents, between 8.53 and 10.86% Fe. Soils developed either on loess or tertiary clay parent rocks (halomorphic soils, some marshy humogleys and vertisols) have shown a wider range of results (1.33-4.65% Fe) with a shift of results towards average values. The majority of the investigated soils that have fallen within the group between 3.00 and 4.96% Fe were represented by pseudogley, eugley luvisol, fluvisol, eutric cambisol, ranker and rendzina. Semigley and chernozem have shown a wider range of distribution of results, from 2.18 to 7.72% Fe.Generally, the analyzed soils have shown lower average results compared with the available literature data. Chemical speciation has shown that an average iron content of 84.24%, with the range from 70 to 92%, was primarily associated with residual forms bound to the silicate lithogenic fraction. An average of 12.69%, with the range from 6 to 26%, has been found as Fe-Mn-oxide/hydroxide fraction. Organic-matter-bound iron (1-9%) and exchangeable and carbonate-bound iron (0.09-1.92%) have been present to a lesser extent.

scholarly journals Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Nuno Vale ◽  
Maria João Gouveia ◽  
Gabriel Rinaldi ◽  
Paul J. Brindley ◽  
Fátima Gärtner ◽  
...  
Keyword(s):  
Rational Design ◽  
Large Scale ◽  
Sub Saharan Africa ◽  
Screening Programs ◽  
Drug Of Choice ◽  
Sub Saharan ◽  
New Compounds ◽  
Derivatives Of ◽  
Large Scale Screening ◽  
Selection Of

ABSTRACT Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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 Mixture of Experts for Predicting Antibody-Antigen Binding Affinity from Antigen Sequence

2019 ◽  
Author(s):  
Srivamshi Pittala ◽  
Chris Bailey-Kellogg
Keyword(s):  
Binding Affinity ◽  
Large Scale ◽  
Vaccine Development ◽  
Predictive Accuracy ◽  
Scale Up ◽  
Antigen Binding ◽  
Mixture Of Experts ◽  
Large Sets ◽  
Wide Range ◽  
Antigen Variant

AbstractAntibodies provide a key mode of defense employed by the immune system to fight disease, so eliciting potent antibodies is one of the main goals in vaccine development. Antibodies are also being conceived as powerful therapeutic agents, so engineering potent antibodies is one of the main goals in biologic drug development. The power of antibodies lies in their affinity and specificity in recognizing their cognate antigens. Unfortunately, experimental techniques to determine antibody-antigen binding affinities are difficult to scale up to large sets of new antibodies and antigens. Though computational methods are suitable for large-scale prediction, current methods lack sufficient accuracy. Here, we address the problem of predicting the binding affinity of an antibody against an antigen variant based on the amino acid sequence of that antigen variant. We develop a mixture of experts approach that learns models for individual antibodies against some antigen variants, and then combines information across the antibodies in order to make accurate predictions for a wide range of new variants. In evaluation on a dataset consisting of 52 antibodies and 608 strains of HIV, the predictive accuracy of our approach is demonstrated to be significantly better than that of an existing approach. Our method provides a fast and accurate way to predict antibody-antigen binding affinity, which has the potential to expedite the study of antibody-antigen interactions for vaccine design and therapy.

Materials Technology and the Engineer

1972 ◽  
Vol 186 (1) ◽  
pp. 281-287
Author(s):  
A. G. Quarrell
Keyword(s):  
Large Scale ◽  
Laboratory Experiments ◽  
Present Situation ◽  
Scale Production ◽  
Future Trends ◽  
Large Scale Production ◽  
Wide Range ◽  
Improved Methods ◽  
Selection Of ◽  
Suitable Process

Never has the engineer had so many materials from which to choose when designing new machines or new structures. Improved metallurgical knowledge has enabled greatly improved alloys to be developed, the demands of aero-space have stimulated developments in ceramics and in composite materials; whilst advances in organic chemistry have led to a wide range of plastics suitable for applications which range from throw-away containers to constructions for which metals or natural materials were previously used. In addition, improved methods are continuously leading to better materials and more reliable components and the selection of the most suitable process for a given application becomes increasingly difficult. Materials technologists and engineers depend very much on each other. Engineers rely upon materials technologists for materials with properties appropriate for particular applications; materials technologists depend upon engineers to design the machines that enable laboratory experiments to be translated into large-scale production. A review of the present situation will be followed by a discussion of future trends and of future co-operation between engineers and materials technologists.

Screening, Production and Partial Characterization of a Thermostable Laccase from Trametes sp. Isolate B7 with Biotechnological Potentials

2019 ◽  
pp. 1-16
Author(s):  
Benjamin Vandelun Ado ◽  
Tivkaa Joseph Amande ◽  
Esther E. Ebah ◽  
Daniel Malo Mabitine
Keyword(s):  
Large Scale ◽  
Trichoderma Viride ◽  
Laccase Production ◽  
Synthetic Dyes ◽  
Phenol Red ◽  
Rhizopus Stolonifer ◽  
Optimum Stability ◽  
Wide Range ◽  
Large Scale Screening

The search for efficient and green oxidation technologies has increased interest in utilization of laccases in non conventional methods. Laccases catalyze a wide range of substrates due to low substrate specificity and strong oxidative potentials. Challenges to large-scale enzyme utilization include, low enzyme activity and instability which restrict use in many areas of biotechnology. In the study, 59 fungi comprising Aspergillus niger (40%), Trichoderma harzianum (31%), Aspergillus flavus (9.0%), Trichoderma viride (5.0%), Fusarium oxysporum (5.0%), Rhizopus stolonifer (5.0%), Trametes sp. (3.0%) and Aspergillus nidulans (2.0%) were isolated and screened for laccase production. Plate screening test showed 57.5%, 34.0% and 8.5% of fungi were laccase-positive on ABTS, Guaiacol, and α-naphthol agar respectively. Isolates were further screened in liquid cultures, and the highest laccase producer identified molecularly. Trametes sp isolate B7 was selected for solid state fermentation (SSF). Laccase production in SSF was highest at pH 5.0 (2356 U/mL). The purified laccase showed high activity (pH 3.0 - 6.0) and stability (pH 3.0 - 8.5) using ABTS. It was active (20 - 80°C) and thermostable (30 - 80°C) with optimum stability at 70°C (100% for 1 hour). The percentage decolourization of Phenol red were 28% and 36% using 1000 U/mL and 2000 U/mL crude laccases respectively. Similarly, RBBR (100%), Congo red (75%) and Malachite green (62%), and 77.4%, 64% and 28% were decolourized using 1000 U/mL and 2000 U/mL crude laccases respectively. ABTS agar was very reliable in large-scale screening for laccase which possessed thermostable property and degraded synthetic dyes without use of enzyme mediators. These attribute made the enzyme suitable for application in industry and biotechnology.

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