Advances in High Content Screening for Drug Discovery

Abstract

Cell-based target validation, secondary screening, lead optimization, and structure-activity relationships have been recast with the advent of HCS. Prior to HCS, a computational approach to the characterization of the functions of specific target proteins and other cellular constituents, along with whole-cell functions employing fluorescence cell-based assays and microscopy, required extensive interaction among the researcher, instrumentation, and software tools. Early HCS platforms were instrument-centric and addressed the need to interface fully automated fluorescence microscopy, plate-handling automation, and seamless image analysis. HCS has since evolved into an integrated solution for accelerated drug discovery by encompassing the workflow components of assay and reagent design, robust instrumentation for automated fixed-end-point and live cell kinetic analysis, generalized and specific BioApplication software (Cellomics, Pittsburgh, PA) modules that produce information on drug responses from cell image data, and informatics/bioinformatics solutions that build knowledge from this information while providing a means to globalize HCS throughout an entire organization. This review communicates how these recent advances are incorporated into the drug discovery workflow by presenting a real-world use case.

A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid β Protein Interactions with Its Receptor CD36

“…HCS uses a powerful automated fluorescent microscope to capture a large number of images per field, allowing thousands of cells to be imaged in one experiment (22). The resulting data can be resolved into single cell analyses allowing a detailed examination of the effects of treatments on the cells.…”

Morphological Evaluation of Nonlabeled Cells to Detect Stimulation of Nerve Growth Factor Expression by Lyconadin B

“…2 Image-based assays enable rapid and exhaustive evaluations of detailed cellular responses. However, because most HCA requires invasive fluorescent staining, such assays tend to be limited to end-point measurements.…”

Current approaches and future role of high content imaging in safety sciences and drug discovery

“…the term high content imaging (HCI) is used to describe automated microscopy combined with image analysis approaches to simultaneously quantify multiple phenotypic and/or functional parameters in biological systems (Giuliano et al, 1997(Giuliano et al, , 2003Abraham et al, 2004). typically, multiple morphological (e.g., cell shape, membranes, nuclei, mitochondria) or functional (e.g., signal transduction, gene expression, metabolism) features in either a cell, cell system or lower model organism are labeled using probes (e.g., fluorescent dyes, antibodies, gene reporters), automatically imaged and quantified by imaging analysis algorithms.…”