What is High Throughput Screening (HTS)?

Drug discovery is a highly complex and multidisciplinary process in pharmaceutical development. The identification of various modulators of molecular targets is a mainstay of this activity. Increasingly, High Throughput Screening (HTS) which involves modern robotics, data processing and control software and certain sensitive detectors, is being used to identify new chemical probes of biological pathways, cell functions and genes in which the relationships between chemical structures and biological activities can be comprehensively delineated. In the competitive pharmaceutical industry, the time from drug development to clinical trial is becoming increasingly pressured. The traditional pharmaceutical research approach can no longer fulfill the intense demands of this drug development schedule. HTS uses laboratory automation to collect a vast amount of pharmacological data such as enzymatic activity and ELISA from the primary screen and reliably profiles the range of biological activities which becomes a large chemical library. The availability of chemical libraries and robotic systems for bioassay allows synthesis and testing of hundreds and even thousands of compounds in a day. Through this process, researchers can rapidly and effectively identify compounds, antibodies or genes which modulate a particular bio-molecular pathway. Hence, this can maximize the probability of success and also greatly reduce the time and cost of drug development. Most importantly, a large-scale cell biology and compounds library is thus developed for higher predictability of clinical efficacy.

HTS Development for Western Drug Discovery

Screening for new pharmaceutical drugs consists of three components: targets, compounds and assays. Genomics and combinational chemistry dramatically increase the range of biological targets and compounds available for screening, which overwhelm the capacity of existing assays. Researchers have put much effort in assay development for HTS. The goals include increased throughput, miniaturization to minimize sample consumption, and the ability to monitor biological phenomena beyond the traditional areas of ligand binding and enzyme activity. Drug discovery has evolved originally from relying a great deal on serendipity in the 1950s and 1960s, to a more structured approach in the 1980s which looked into detail at agonist-receptor interactions. Nowadays, the modern approach to drug discovery has been disease-oriented. Scientists have attempted increase their knowledge about a disease and its causes, and use this knowledge as a way to screen some suitable compounds for treating the disease. Advances in molecular and cellular biology, genetics and genomics have helped in the discovery of new drugs. HTS is usually involved in the early stage of a drug's development especially after a target has been identified and is currently one of the few areas in the whole drug discovery process where significant time savings can be made in finding candidate drugs. For this reason, HTS has been widely adopted by all major Western pharmaceutical companies.

Use of HTS in Chinese Medicine

HTS has also been used for the classification and identification of crude materials making up traditional Chinese medicine. The herbs are separated into different components by primary purification, chromatography and then the structural and chemical properties of each component has to be confirmed; the data is then entered into the crude compound library as the screening platform. Traditional Chinese medicine has a long history in the treatment of various disorders such as neurodegenerative disease, cancer and stroke. HTS ensures an effective and a vast range of target-based drug screening strategies which increases the prospects of obtaining biological and clinical relevance to specific disease states.

Limitation of HTS in Chinese Medicine

HTS tests compounds at a single concentration which is not suitable for traditional Chinese medicine as a wide range of doses are used in different stages of diseases. The dosage of various herbs can therefore critically affect the efficacy of the prescription. In the Western medical point of view, the basis of these observations is that ligands affecting biological systems have optimal ranges of activity, which gives rise to a complex and variable concentration-effect relationship. This well-known property of chemical compounds in biological systems requires a dose-specific screening to achieve a desirable biological effect either in basic or clinical application.

Conclusion

HTS has been used for drug discovery for over a decade. It is an important and effective tool used in Western pharmaceutical development. It might also prove useful to screen Chinese herbs. However, more advanced screening technologies should be developed to address the limitation of traditional HTS for traditional Chinese medicine. For example, quantitative HTS (qHTS) methodology can be applied concerning this issue.

Suggested Reading:

Inglese J., et al. Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries. PNAS103, 11473-11478 (2006). Abstract

Compiled and edited by:

Jennifer Eagleton, BA, MA (Asian Studies), Integrated Chinese Medicine Holdings Ltd. Stan Man, Integrated Chinese Medicine Holdings Ltd.