What is High-Throughput Screening?
Author: Laura Frigo
Graphical Abstract
The purpose of this paper is to elucidate what high-throughput screening is and how it is utilized in pharmaceutical and biotechnology companies, as well as in basic and applied research. Some of the advantages and disadvantages brought by this relatively new approach will also be presented here.
High-throughput screening, or high-throughput technology, refers to a well-established approach that involves the use of miniaturized assays, automation, robotics, and large-scale data analysis in order to discover and investigate new lead compounds (Mayr and Bojanic 2009). The latter are chemical compounds characterized by certain properties such as size, shape, and solubility, that make them good precursors for the discovery of new drugs (Hefti 2008).
This new method was first introduced in the early/mid 1990s and specifically in the past twenty years has significantly evolved and improved (Mayr and Bojanic 2009). Some of the first lead compounds to be identified using high-throughput screening include the reverse transcriptase inhibitor Viramune and the protein kinase C beta-isoform selective inhibitor (Entzeroth et al., 2009). It is also particularly interesting to note that the total number of compounds that can be screened at the same time has increased over the years, particularly as a result of the introduction of more advanced automated systems. Moreover, high-throughput screening allows to test 10,000-100,000 compounds per day and is differentiated from ultra-high-throughput screening which allows to test over 100,000 compounds every day (Entzeroth et al., 2009).
The main application of high-throughput screening is drug discovery which entails the identification of chemical compounds that are observed to interact with specific biological targets of interest. Initially, the compounds being analyzed are assayed against several well-characterized targets in order to understand the mechanism of different processes such as enzyme activation and/or inhibition, modulation of the interaction of macromolecules (proteins, nucleic acids etc.), and more. It then follows a process referred to as “hit-to-lead” which entails the modification of the identified compounds characterized by the desired activities, through the use of different chemical approaches; the purpose of this step is to make the compounds more efficient and to optimize their drug-like properties (Entzeroth et al., 2009).
High-throughput screening requires the use of compound libraries that are composed of molecules with small molecular weight and are used for the identification of hits obtained through the screening process (Hughes et al. 2011).
The main contribution that high-throughput screening brought is that it allows to screen numerous samples at the same time, as previously stated. Consequently, the handling time is also reduced. The latter, however, takes into consideration the time required to complete all the steps needed, starting from the nomination of a target for high-throughput screening to the delivery of a list of lead compounds that can be used to initiate a medicinal chemistry study. Interestingly, there is evidence showing that the screening process occupies just about 10% of the total handling time; this is possible thanks to the use of automated systems that make the entire screening process much faster. On the other hand, the analysis and interpretation of the obtained results, and the preparation of instrumentation and assays, is what take the most time (Mayr and Bojanic 2009).
High-throughput screening also allows to significantly reduce the amounts of reagents used and to reduce the errors that could be easily done if the assays were to be performed manually.
It is also necessary to note that high-throughput screening requires the use of equipment that is highly expensive, including automated plate handling, readout systems, etc. (Mayr and Bojanic 2009).
Resources
References
- Entzeoth, M., Flotow, H., Condron, P. (2009) Overview of high-throughput screening. Current protocols in pharmacology, 44(1)
- Hefti, F. F. (2008) Requirements for a lead compound to become a clinical candidate. BMC Neurosci, 9 Suppl 3, S7.
- Hughes, J. P., S. Rees, S. B. Kalindjian & K. L. Philpott (2011) Principles of early drug discovery. Br J Pharmacol, 162, 1239-49.
- Mayr, L. M. & D. Bojanic (2009) Novel trends in high-throughput screening. Curr Opin Pharmacol, 9, 580-8.
Questions
- What is it? High-throughput screening is an automated approach that allows to identify the effect of several compounds in biological and/or chemical assays.
- Why is it important? It’s important because it allows to screen several compounds (10,000-100,000 per day) at the same time.
- What are some examples of pros in HTS? Reduces time for drug discovery, uses smaller volumes of reagents, easier than doing it manually (less chances for errors).
- What are some examples of cons in HTS? Requires expensive equipment, it is technically challenging (good knowledge of the equipment is required)