Special Issue "High-throughput Screening"

Guest Editor
Dr. Florian Hollfelder
Department of Biochemistry, 80 Tennis Court Road, 3.84 Sanger Building, GB, Cambridge CB2 1GA, United Kingdom
Website: http://www.bioc.cam.ac.uk/uto/hollfelder.html
E-Mail:
Phone: +44 1223 766048 (lab)
Fax: +44 1223 766002

Dear Colleagues,

In addition to being the workhorse of the pharmaceutical industry, high-throughput screening is becoming a more and more central experimental approach in diverse research areas ranging from genomics, proteomics to systems and synthetic biology. The idea of characterizing entire ensembles of genes, proteins, small molecule or organismal repertoires is attractive when the complexity of a system defies straightforward understanding and rational manipulation.

In contrast to selection approaches that obey a ‘first-past-the-post’ logic, screening quantitatively measures one or more experimental parameters for the entire library. The knowledge about an entire library may give rise to structure-activity relationships and allows a more informed choice about which molecules to select e.g. for further rounds of evolutionary improvements.

Accessibility of these approaches to a wider circle of experimentalists has been driven by technological advances, specifically miniaturization and advances in detection systems. This issue will focus on the technical advances that give insight into property spaces and combine it with an outlook towards the potential of such massively parallel experimentation in Chemistry and Biology.

Florian Hollfelder, Ph.D.
Guest Editor

Submission

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• DNA library
• Encoding /decoding
• In vitro compartmentalisation
• Systems biology
• Synthetic biology

Manuscript ID: Molecules-hts-20090818-Demirci-us
Type of Paper: Review
Title: Cell Printing As A Novel Method For High Throughput Drug Screening
Authors: F. Xu¹, U. Demirci^1,2
Affiliation: ¹ Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
² Harvard-MIT Health Sciences and Technology, Cambridge, MA, USA; E-Mails: fxu2@rics.bwh.harvard.edu, utkan1@gmail.com
Abstract: It is important to identify drug candidates for drug treatment of different tissue/organ diseases. However, there are over a million drug candidates available and testing millions of drugs one by one is a forbidding task with current technologies. To achieve high throughput drug testing, the biggest challenge is to create the tissue construct models at high throughput. These model constructs should mimic the in vivo environment and function of the native tissue and vary minimally from one model tissue construct to another. The emerging high throughput cell printing technique offer solutions to overcome the above described challenge of this high impact field. In this paper, we will present state-of-art on the application of cell printing for high throughout drug screening.

Manuscript ID: Molecules-hts-20090820-Langner-pl
Type of Paper: Review
Title: Fluorescence Techniques for a Membrane Potentials Determination in High-Throughput Screening.
Authors: Magdalena Przybyło, Tomasz Borowik and Marek Langner
Affiliation: Laboratory for Biophysics of Macromolecular Aggregates, Institute of Biomedical Engineering and Measurements, Wroclaw Technical University, Wroclaw, Poland; E-Mail: marek.langner@pwr.wroc.pl
Abstract: The characterization of small molecules, when selecting compounds for pharmacological applications and/or determining their toxicity, requires the identification and evaluation of several predictive parameters. A number of them are correlated with the compound interaction with biological membranes and/or capacity to cross them. Knowledge of the extend of adsorption, partition coefficient, permeability along with the compound ability to alter membrane properties are critical for such studies. Lipid bilayers are frequently used as an adequate experimental model of a biological membrane despite their simple structure and a limited number of components. A significant number of the biologically relevant lipid bileyer properties are related to its electrostatics. Three electrostatic potentials have been defined for the lipid bilayer; intrinsic or induced surface electrostatic potential, dipole potential and membrane potential. Each of them has been measured with dedicated, and in many cases technically advanced, methodologies. The large diversity of methods, complicated measuring protocols and technically demanding instrumentation results with the situation where the development of efficient HTS approaches for complete characterization of membrane electrostatics was practically impossible. However, rapid development of fluorescence based measurement techniques accompanied by a rapid growth in diversity and number of dedicated fluorescence probes created a situation when an experimental approach to characterize a lipid bilayer electrostatics is now feasible. Technically advanced, compact and automated workstations, capable to measure practically all fluorescence parameters, are now available. Therefore, the proper selection of fluorescence probes together with measuring procedures can be designed to evaluate drug candidates from the point of view of their ability to alter membrane electrostatics. In the paper we present critical review of an available fluorescence methods useful for the membrane electrostatics evaluation and discuss the feasibility of their adaptation to HTS procedures. The significance of the presented methodology is even greater considering the rapid growth of advanced drug formulations where electrostatics is an important parameter for production processes and determines a pharmacokinetics of the product. Finally, the potential of membrane electrostatics to emerge as a viable pharmacological target is indicated and fluorescence techniques capable to evaluate this potential are presented.

Manuscript ID: Molecules-hts-20090929-Goueli-us
Type of the Paper: Review
Author: Said A.Goueli
Affiliation: Dept. of Pathology and Lab. Medicine, School of Medicine and Public Health,University of WisconsinMadison, WI 53711, USA; E-Mail: said.goueli@promega.com
Abstract: As the role of protein kinases in regulating normal and abnormal cell growth became well appreciated, protein kinases are recognized as ideal drug targets candidates. The search for such drugs starts with screening of large collection of compounds to find the ideal compound with proven selectivity, potency and low toxicity. To achieve this goal, an ideal kinase assay that is homogenous, robust, sensitive, universal, and flexible to be performed under wide range of assay conditions is essential. Furthermore, it is desirable to have one platform technology that can be used for compound screening, hit lead identification, and enzyme profiling during the various stages of drug discovery prior to clinical investigations. We will review current assays that have gained widespread acceptance and describe the strengths and weaknesses of each assay.