scholarly journals Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery

2006 ◽  
Vol 361 (1467) ◽  
pp. 413-423 ◽  
Author(s):  
Tom L Blundell ◽  
Bancinyane L Sibanda ◽  
Rinaldo Wander Montalvão ◽  
Suzanne Brewerton ◽  
Vijayalakshmi Chelliah ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Structural Biology ◽  
Genome Sequencing ◽  
High Throughput ◽  
Structure Determination ◽  
Target Identification ◽  
Three Dimensional ◽  
Central Place ◽  
Lead Discovery ◽  
High Throughput Crystallography

Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding.

High-Throughput Crystallography and Its Applications in Drug Discovery

2017 ◽  
pp. 153-179
Author(s):  
H. Nar ◽  
D. Fiegen ◽  
S. Hörer ◽  
A. Pautsch ◽  
D. Reinert
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Crystallography

scholarly journals Beta-hairpin hydrogels as scaffolds for high-throughput drug discovery in three-dimensional cell culture

2017 ◽  
Vol 535 ◽  
pp. 25-34 ◽  
Author(s):  
Peter Worthington ◽  
Katherine M. Drake ◽  
Zhiqin Li ◽  
Andrew D. Napper ◽  
Darrin J. Pochan ◽  
...  
Keyword(s):  
Cell Culture ◽  
Drug Discovery ◽  
High Throughput ◽  
Three Dimensional ◽  
Beta Hairpin ◽  
Dimensional Cell

scholarly journals Development of a High-Throughput Three-Dimensional Invasion Assay for Anti-Cancer Drug Discovery

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e82811 ◽  
Author(s):  
Nikki A. Evensen ◽  
Jian Li ◽  
Jie Yang ◽  
Xiaojun Yu ◽  
Nicole S. Sampson ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Three Dimensional ◽  
Cancer Drug ◽  
Invasion Assay ◽  
Cancer Drug Discovery ◽  
Anti Cancer

Single Crystal X-Ray Structural Determination: A Powerful Technique for Natural Products Research and Drug Discovery

2012 ◽  
Vol 545 ◽  
pp. 3-15
Author(s):  
Hoong Kun Fun ◽  
Suchada Chantrapromma ◽  
Nawong Boonnak
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Single Crystal ◽  
Natural Product ◽  
Structure Determination ◽  
Three Dimensional ◽  
X Ray ◽  
Powerful Technique ◽  
Determination Of Absolute Configuration

Drug discovery from natural products resources have been extensively studied. The most important step in the discovery process is the identification of compounds with interesting biological activity. Single crystal X-ray structure determination is a powerful technique for natural products research and drug discovery in which the detailed three-dimensional structures that emerge can be co-related to the activities of these structures. This article shall present (i) co-crystal structures, (ii) determination of absolute configuration and (iii) the ability to distinguish between whether a natural product compound is a natural product or a natural product artifact. All these three properties are unique to the technique of single crystal X-ray structure determination.

scholarly journals Assay Establishment and Validation of a High-Throughput Screening Platform for Three-Dimensional Patient-Derived Colon Cancer Organoid Cultures

2016 ◽  
Vol 21 (9) ◽  
pp. 931-941 ◽  
Author(s):  
Karsten Boehnke ◽  
Philip W. Iversen ◽  
Dirk Schumacher ◽  
María José Lallena ◽  
Rubén Haro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Single Cells ◽  
Three Dimensional ◽  
Compound Screening ◽  
Organoid Cultures ◽  
Screening Platform ◽  
Disease Specific

The application of patient-derived three-dimensional culture systems as disease-specific drug sensitivity models has enormous potential to connect compound screening and clinical trials. However, the implementation of complex cell-based assay systems in drug discovery requires reliable and robust screening platforms. Here we describe the establishment of an automated platform in 384-well format for three-dimensional organoid cultures derived from colon cancer patients. Single cells were embedded in an extracellular matrix by an automated workflow and subsequently self-organized into organoid structures within 4 days of culture before being exposed to compound treatment. We performed validation of assay robustness and reproducibility via plate uniformity and replicate-experiment studies. After assay optimization, the patient-derived organoid platform passed all relevant validation criteria. In addition, we introduced a streamlined plate uniformity study to evaluate patient-derived colon cancer samples from different donors. Our results demonstrate the feasibility of using patient-derived tumor samples for high-throughput assays and their integration as disease-specific models in drug discovery.

A Framework for Optimizing High-Content Imaging of 3D Models for Drug Discovery

2020 ◽  
Vol 25 (7) ◽  
pp. 709-722
Author(s):  
Judith Wardwell-Swanson ◽  
Mahomi Suzuki ◽  
Karen G. Dowell ◽  
Manuela Bieri ◽  
Eva C. Thoma ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Immune Cell ◽  
Three Dimensional ◽  
Morphological Characteristics ◽  
Drug Efficacy ◽  
3D Models ◽  
Routine Practice ◽  
High Content Imaging

Three-dimensional (3D) spheroid models are rapidly gaining favor for drug discovery applications due to their improved morphological characteristics, cellular complexity, long lifespan in culture, and higher physiological relevance relative to two-dimensional (2D) cell culture models. High-content imaging (HCI) of 3D spheroid models has the potential to provide valuable information to help researchers untangle disease pathophysiology and assess novel therapies more effectively. The transition from 2D monolayer models to dense 3D spheroids in HCI applications is not trivial, however, and requires 3D-optimized protocols, instrumentation, and resources. Here, we discuss considerations for moving from 2D to 3D models and present a framework for HCI and analysis of 3D spheroid models in a drug discovery setting. We combined scaffold-free, multicellular spheroid models with scalable, automation-compatible plate technology enabling image-based applications ranging from high-throughput screening to more complex, lower-throughput microphysiological systems of organ networks. We used this framework in three case studies: investigation of lipid droplet accumulation in a human liver nonalcoholic steatohepatitis (NASH) model, real-time immune cell interactions in a multicellular 3D lung cancer model, and a high-throughput screening application using a 3D co-culture model of gastric carcinoma to assess dose-dependent drug efficacy and specificity. The results of these proof-of-concept studies demonstrate the potential for high-resolution image-based analysis of 3D spheroid models for drug discovery applications, and confirm that cell-level and temporal-spatial analyses that fully exploit multicellular features of spheroid models are not only possible but soon will be routine practice in drug discovery workflows.

scholarly journals PolySNAP: a computer program for analysing high-throughput powder diffraction data

2004 ◽  
Vol 37 (4) ◽  
pp. 658-664 ◽  
Author(s):  
Gordon Barr ◽  
Wei Dong ◽  
Christopher J. Gilmore
Keyword(s):  
Computer Program ◽  
Powder Diffraction ◽  
High Throughput ◽  
Three Dimensional ◽  
Principal Component ◽  
Visualization Tools ◽  
Diffraction Patterns ◽  
Pure Phases ◽  
Related Compounds ◽  
High Throughput Crystallography

In high-throughput crystallography experiments, it is possible to measure over 1000 powder diffraction patterns on a series of related compounds, often polymorphs or salts, in less than one week. The analysis of these patterns poses a difficult statistical problem. A computer program is presented that can analyse such data, automatically sort the patterns into related clusters or classes, characterize each cluster and identify any unusual samples containing, for example, unknown or unexpected polymorphs. Mixtures may be analysed quantitatively if a database of pure phases is available. A key component of the method is a set of visualization tools based on dendrograms and pie charts, as well as principal-component analysis and metric multidimensional scaling as a source of three-dimensional score plots. The procedures have been incorporated into the computer programPolySNAP, which is available commercially from Bruker-AXS.

High-throughput crystallization and structure determination in drug discovery

2002 ◽  
Vol 7 (3) ◽  
pp. 187-196 ◽  
Author(s):  
Lance Stewart ◽  
Robin Clark ◽  
Craig Behnke
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Structure Determination

An approach to rapid protein crystallization using nanodroplets

2002 ◽  
Vol 35 (2) ◽  
pp. 278-281 ◽  
Author(s):  
B. D. Santarsiero ◽  
D. T. Yegian ◽  
C. C. Lee ◽  
G. Spraggon ◽  
J. Gu ◽  
...  
Keyword(s):  
Protein Structure ◽  
Drug Discovery ◽  
High Throughput ◽  
Structural Genomics ◽  
Structure Determination ◽  
Protein Crystallization ◽  
Protein Structure Determination ◽  
Automated System ◽  
Order Of Magnitude ◽  
Time Required

An approach that enables up to a two order of magnitude reduction in the amount of protein required and a tenfold reduction in the amount of time required for vapor-diffusion protein crystallization is reported. A prototype high-throughput automated system was used for the production of diffraction-quality crystals for a variety of proteins from a screen of 480 conditions using drop volumes as small as 20 nL. This approach results in a significant reduction in the time and cost of protein structure determination, and allows for larger and more efficient screens of crystallization parameter space. The ability to produce diffraction-quality crystals rapidly with minimal quantities of protein enables high-throughput efforts in structural genomics and structure-based drug discovery.

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