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HIGH-THROUGHPUT SCREENING FOR DRUG DISCOVERY. Akash Kalra, Deepak Kalra, Eshant Duggal

HIGH-THROUGHPUT SCREENING FOR DRUG DISCOVERY.

Akash Kalra, Deepak Kalra, Eshant Duggal

International Journal of Natural Product Science 2012: Spl Issue 1:124.

Abstract(RBIP-124)

High Throughput Screening: to screen larger libraries in order to continue the pipeline for Drug Discovery. For a number of years, HTS assays have been run in the standard 96-well micro plate (Working volume of up to 250 μL). The current goal of most companies is to move beyond this format to higher- d e n s i t y, lower-volume formats (e.g., 384- and 1536-well micro plates). Compounds are only tested in duplicate (an increasing number of companies are using singlet’s), and usually at one concentration (most often in the 1–10 μM range for combinatorial chemistry libraries). If a “hit” (positive) is discovered, more accurate secondary assays are used for follow-up, quantification, and I C50 calculation. HTS uses standard assay types known to most biological and biochemical scientists (e.g., ELISA, proliferation/cytotoxicity assays, reporter assays, and binding assays). However, adaptations of these assays have emerged to facilitate throughput and relieve robotic complexity. Screeners define assays as either heterogeneous or homogeneous. Heterogeneous assays require steps that go beyond simple fluid additions, incubations, and reading (e.g., filtration, centrifugation, and plate washing steps). Homogeneous assays require only additions and incubations followed by reading.
Assays can be broadly divided into two branches:
1. Pure Protein Assays: In this type every compound screened should have equal access to the target.
2. Cell Based Assays: In this type the readouts of cell based screens may rely on reporter gene systems.
Recent advances in HTS are use of Robotics has been important to achieve the desired screening rates, as well as relieving scientific staff from tedious work. A new and improved industrial approach to HTS robotics is the Allegro technology. Similar to assembly-line manufacturing, micro plates are passed down a line in serial fashion to consecutive processing modules. High throughput enabled technologies will be fundamental to more efficient clinical trials by providing the means to base the studies on well-characterized surrogate disease-markers in genotype-selected populations. HTS has revolutionized compound screening. However, it has also introduced new challenges to the drug discovery and development process. Just a small fraction of primary hits generated by the HTS can easily overwhelm traditional follow-up testing, therefore creating new bottlenecks in the drug discovery process. Thus, it is now time to explore the application of the high throughout technologies to those new bottlenecks in the areas of medicinal chemistry, structural biology, pharmacology, ADME studies, and toxicology.
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