Further experts from industry and academia will present their current projects and challenges. A poster session in the afternoon break and a get-together in the evening will provide plenty of time for networking. Program and more infos here. Break ground on new discoveries. The ASBMB Annual Meeting is where leading experts and scientists at all points on their career trajectories convene to share new research.
Attend inspiring lectures and hands-on workshops, connect with peers in the biochemistry and molecular biology community, and gain inspiration to take back to the lab. Join us at the pinnacle of scientific exchange April 6—9 in Orlando. Chemical biologists from all parts of Europe and overseas come together to present and discuss the latest achievements in cutting edge chemical sciences.
More infos on the conference here. The Novel Antimicrobials and AMR Diagnostics conference is a platform for SMEs, start-ups, big pharma, academia, investors and public institutions to discuss strategies and the specific challenges faced by SMEs in bringing new antimicrobial treatments and diagnostics to the market. More information here. Looking forward to meeting you there! Ladies and Gentlemen, Let us shape the future together. We therefore invite you to the Berlin Science Week - to our event Future 4. Juni , Berlin.
Get to know Berlin's places of the future and meet interesting companies that will shape the products of the future with you. Get in touch with scientific institutions that will also put your ideas of tomorrow into practice.
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Find out about the places where all the knowledge and skills come together. Keynote lecture: "What does theory say: How will we work in the future? In which areas will our working environments change? Hoppe, Humboldt University Berlin. Panel discussion: "What does a modern future location have and need? More infos.
For more information see here: www. For more information see here: ascb-embo Recent in-silico approaches will be discussed as well as their applications in academic drug discovery efforts including drug repurposing and high-throughput combinatorial approaches to guide the biologist to select appropriate high-quality probes for their experiments. For more information: This session is a unique opportunity to network with other neuroscientists and find out about opportunities to benefit from free training and research visits to high end laboratories across Europe offering access to the latest technologies including cryo-Electron Microscopy, Xray spectroscopy, NMR, Nanobody discovery, selective plane illumination microscopy SPIM , super resolution microscopy, multi-modal molecular imaging and high throughput drug screen technologies.
Professor Radu Aricescu from the University of Cambridge will present his latest research in the area of GABA receptor structure and function allowing fresh insights into inhibitory neurotransmission. He will share his experience in working with European research infrastructures and how open access to high-end technologies can enable cross-disciplinary, pioneering research projects.
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For more information, please see here. The session will take place on Sunday, am. More Information. More information. Bahne Stechmann will give an early bird session on "New European research infrastructures in imaging, structural biology and compound screening: how to take advantage as a researcher? Home Newsroom Events. Katja Herzog at the Berlin Science Week.
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- Composition and applications of focus libraries to phenotypic assays.
Juni , Berlin Get to know Berlin's places of the future and meet interesting companies that will shape the products of the future with you. We would like to draw your special attention to two highlights: Keynote lecture: "What does theory say: How will we work in the future?
Hoppe, Humboldt University Berlin Panel discussion: "What does a modern future location have and need? Examining biological annotations for the entire dataset including activity outside the extremes can rescue weak activity. A Depicted are three cases where compounds modulate cell signaling. In case 1, a compound shows high activity through, for example, activation of apoptosis.
In case 2, three compounds are annotated to targets known to function in the same signaling pathway but each compound shows weak activity in the assay. B While compounds in case 1 and 3 are easily captured using standard statistical thresholds, compounds in case 2 may only be rescued by examining the entire dataset and considering the target annotations in the context of biological pathway analysis.
C Plot representing the aggregate effect of compounds perturbing a pathway to identify weakly active compounds case 2. Each circle on the plot represents a pathway. The x-axis represents the aggregate effect of compounds hitting targets from the same pathway.
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For example, case 2 is depicted as having three compounds that individually show weak activity but are annotated as operating in the same pathway. Using such an approach, relevant biological processes with subtle effects can be identified. Compounds that modulate upstream nodes in a pathway may have much smaller effects on the assay signal but these weak hits could be rescued by considering if their target annotations place them in the same pathway Figure 3.
In this way the entire dataset can be considered independent of potency or activity threshold values and weak activity can be considered if this activity significantly clusters within specific pathways Figure 3 Subramanian et al. In other words, the aggregate effect on a biological pathway level is of highest interest as opposed to individual compound activities. Such an analysis enables: 1 identification of mechanisms of interest: known or unknown pathways; 2 identification of new biological endpoints to help validate the observation e.
The use of prior biological knowledge is particularly powerful when screening with focused libraries where the MoA of compounds is known. The identification of novel pathways and processes can help establish additional endpoints to be measured in a screening funnel or be used as surrogate readouts—ones that correlate with the phenotype of interest—and that may be more amenable to a large scale HTS campaign thus enabling access to a much larger chemical space.
For example, if in a given focused library screen, perturbing the JNK pathway has a significant outcome in the measured phenotype, then PD biomarkers within the JNK pathway can be selected as orthogonal measurements in a screening funnel. Alternatively, such an observation can be used to help validate the screen due to prior knowledge that the JNK pathway is implicated in the biology being measured.
Ultimately, the success of any screen depends on the interpretability of the results where the combination of a good compound collection, measuring the right biological endpoints, and application of analytical approaches will increase the chances of identifying biologically relevant leads, particularly if challenges such as polypharmacology and pleiotropic effects of molecules are addressed and taken into consideration. More and more evidence points to the fact that drugs previously perceived to be selective actually exert their effect through more than one target Hopkins, ; Reddy and Zhang, Furthermore, with the advent of genomic technologies such as gene expression profiling, it has become evident that even drugs with high target selectivity have pleiotropic effects by modulating diverse downstream signaling events Lamb, ; Dobbelstein and Moll, This has led to a shift from SAR analysis based on a single endpoint to modeling of multiple target activities Lopez-Vallejo et al.
Therefore, the design and interpretation of focused libraries is shifting to include a combination of computational approaches that merge chemo-informatics, bioinformatics, and systems biology. Polypharmacology presents a challenge in the interpretation of phenotypic screens because it is not necessarily evident which target is contributing to the effect. Furthermore, screening usually takes place at high concentrations, e. If the library contains both optimized bioactive molecules and also blunt scaffolds, screening at such high concentrations favors the polypharmacology of the optimized molecules to be in full display making the results hard to interpret.
This is another reason that a titration-based screening approach should be used when employing MoA libraries, as mentioned above. Polypharmacology can be established a priori by both experimental and computational approaches. Experimentally, biochemical profiling of target classes can give an idea of the selectivity profile for a given molecule.
Similarly, gene expression profiling of compounds can shed light on the processes regulated by the bioactive molecules. Computational approaches to establish polypharmacology of compounds have been developed employing either properties of the ligand or the structure of the targets Houghten et al.
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- Chapter 27 - Biological Monitoring.
In addition, by combining gene expression and protein interaction networks, systems biology based methods are also employed to reverse engineer the upstream targets that best explain the gene expression profile i. All of this information can then be leveraged to increase the interpretation of the screen as, for example, through pathway-based methods as described above. In addition, the polypharmacology of drugs can be used in the rational design of focused libraries. For example, Gujral et al. The composition and applications of compound libraries is evolving significantly.
Large archives containing analogs for known target classes e. More recently, largely due to the increased use of complicated phenotypic screens—usually limited in throughput and interpretability—smaller libraries will need to be compiled that leverage prior biological knowledge and the polypharmacology and pleiotropism of the compounds. For example, many ex vivo assays such as long-term potentiation or multi-electrode arrays can be employed as phenotypic assays that measure neuronal activity but these assays have extremely low throughput Thomas et al.
Improved strategies to build such libraries coordinated with the development of computational methods to interpret the results are needed. The ever growing body of orthogonal chemical biology datasets will continue to change our understanding of compound properties and how compounds are selected for focus library development. For example, biological profiling may help identify molecule classes, which although chemically distinct, have a common biological mechanism and provide a means for compound repositioning or an understanding of adverse effects Lounkine et al.
Similarly, systematic efforts to understand the toxicity of compounds have resulted in large publicly available datasets with noted examples including data sets from Iconix Biosciences Ganter et al. Optimal employment of these databases requires expert teams of biologists, chemists, and informatics scientists with critical consideration of the source data.
However, the combination of historical and ongoing chemical profiling PubChem, ChembL with improved annotation and data mining tools such as BARD will lead to improved methods to design focused libraries. The authors and editor declare that while they are currently affiliated with Novartis, there has been no conflict of interest during the review and handling of this manuscript.
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors are employees of Novartis and work within the Novartis Institutes of Biomedical Research. We thank W. Adam Hill for critical reading of the manuscript. Amberger, J. Anastasiou, D. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science , — Auld, D. Considerations for the design and reporting of enzyme assays in high-throughput screening applications.
CrossRef Full Text. Baell, J. New substructure filters for removal of pan assay interference compounds PAINS from screening libraries and for their exclusion in bioassays. Bain, J. The selectivity of protein kinase inhibitors: a further update. Basu, S.
Biology-oriented synthesis of a natural-product inspired oxepane collection yields a small-molecule activator of the Wnt-pathway. Besnard, J. Automated design of ligands to polypharmacological profiles.