High-throughput Screening Using Small Molecule Libraries

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Small molecule libraries are most commonly used in drug discovery programs to discover molecules with the greatest activity or inhibitory potential against a particular target.

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In drug discovery, various methods of lead generation exist that give researchers a starting point to develop drugs further and make them as efficacious as possible. High-throughput screening is a practical lead generation technique, as it is able to screen potentially millions of unique compounds against a target using automated biological assays.

Ultra-high-throughput screening, which utilizes microfluidics to test a compound in the space of a small droplet, can be used to carry out as many as 100,000 assays per day.

The main aim of high-throughput screening is to determine the structure-activity relationship of efficacious molecules, in order to allow further optimization of the compound to interact best with the druggable target. By finding molecules that have activity against the desired target, commonalities between them can be discovered and exploited.

High-throughput screening methods are also used to characterize metabolic, pharmacokinetic and toxicological data about new drugs.

Stages of high-throughput screening

High-throughput screening generally consists of several key stages, beginning with target identification, where biomolecules, such as receptors, enzymes or ion channels are identified as a useful target for activation or inhibition.

Following this, assays must be developed that can reliably give qualitative and quantitative information about the activity of the target molecule when exposed to the molecules belonging to the library. This can be streamlined by using known or suspected structure-activity-relationships, previous high-throughput screening rounds, or in silico methods.

Computational techniques are usually also applied in collaboration with high-throughput screening. A large amount of data has been collected regarding the physicochemical properties of small molecules in the preceding century, and modern technology allows for high-throughput screening to be performed in an entirely virtual environment.

Optimization of lead molecules also takes place using software, before the molecules are synthesized and added to the small molecule library for further rounds of high-throughput screening.

Small molecule library creation

The molecules that make up the library come from a variety of sources, such as compound vendors, contract research organizations, or synthesized by the organization performing the high-throughput screening themselves. Purified natural products and extracts make up a large portion of such a library.

Planning and selecting the contents of a small molecule library is a critical step, which is informed by a variety of factors. Several characteristics will be selected for in compounds in the library, including solubility in a carrier solvent and the assay environment at relevant concentrations, availability and ease of synthesis, known non-toxicity or lack of other problematic features, such as the tendency to form covalent bonds with biomolecules, and many others.

If a specific target is known, and the molecular structures that best interact with this target are also known, often from previous rounds of high-throughput screening, then a more focused library is used to further narrow down the candidates in the library to only the most effective.

The focused library will be made up of molecules with similar structure, physical properties, potential energy surfaces, volume, shape, water accessible surface area, dipole moment, and other features, to the most successful candidates from the previous screening.

Further Reading

Last Updated: Nov 1, 2018

Michael Greenwood

Written by

Michael Greenwood

Michael graduated from the University of Salford with a Ph.D. in Biochemistry in 2023, and has keen research interests towards nanotechnology and its application to biological systems. Michael has written on a wide range of science communication and news topics within the life sciences and related fields since 2019, and engages extensively with current developments in journal publications.  


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