Application of High-throughput Drug Screening in New Drug Development

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The principle of high-throughput drug screening is that drugs mostly re-adjust the patient's physiological state by specifically acting on target proteins (receptors, enzymes, ion channels, etc.). High-throughput screening (HTS), using microplates containing compounds (such as enzymes and receptors) and cells as carriers, is a method for screening drug candidates that interact with a target protein from a sample library.

HTS has the advantages of high efficiency and speed in the innovative lead discovery. The basic mode of high-throughput drug screening is to evaluate the biological activity of a large number of samples with a single screening model, and to find samples that are active against a certain target. With the completion of the Human Genome Project (HGP), potential drug targets continue to be discovered, and new drug targets keep emerging, which not only provides opportunities for the discovery of innovative drugs, but also puts forward new requirements for screening efficiency.

1 The basic process of high-throughput drug screening and development of new drugs

Traditional pharmacological research generally firstly studies drug's object effects and then studies the mechanism of action. In contrast, since the result obtained by high-throughput screening is at the molecular or cellular level, in most cases, it can only reflect the mechanism of the sample's action and fails to fully prove its preventive effect on a certain disease, which is an important difference between high-throughput screening and traditional screening methods. The high-throughput screening method starts from the molecular level, and this process is also called reverse pharmacology. The discovery and development of drugs using high-throughput screening methods generally go through the process of primary screening, re-screening, secondary screening, and confirmatory screening.

Primary screening and secondary screening

Primary screening and secondary screening refer to screening samples at the molecular or cellular level to testify a sample's pharmacological activity (or affinity) for the target. After the initial screening, select the active compound, and use a series of concentrations to perform a re-screening of the same model to clarify its action characteristics, activity intensity, and dose-effect relationship on the target, and then find the active compound (sample).

In-depth screening

On the basis of primary screening and secondary screening, the obtained samples are further screened by using different but related molecular and cellular models from the preliminary screening to prove the selectivity, cytotoxicity, and other properties. After in-depth screening, sufficient experimental data are provided for more comprehensive evaluation on the medicinal value of the active compounds. Combining these data with the chemical structure and properties of the active compound, a comprehensive analysis is carried out to determine that the compound with novel structure, function, and development value is the lead compound. At the same time, it can also be combined with tissues, organs, or whole animal models to prove its pharmacological effects and provide a more sufficient experimental basis for samples.

Confirmatory screening

More in-depth and extensive research can be conducted on the lead compounds obtained by in-depth screening or the compounds with the best activity after optimization, including screening of their pharmacological effects, drug metabolism processes, toxicity, and other properties to determine their development potential.

2 The transformation of high-throughput drug screening technology to drug development strategies


The application of new methods and technologies will inevitably have an impact on existing operating methods, especially on the drug discovery process. It is necessary to actively apply new technologies to increase the success rate and screening speed. Currently, route scouting and exploration for preclinical and clinical development has become an important area of interest. However, if the research strategy is not adjusted, the application of new technologies and the development of the research process will be restricted, and even leads to erroneous results.

2.1 Changes in screening strategy

The application of high-throughput drug screening technology has revolutionized drug discovery process. Since the screening method is based on the molecular and cellular level, there are bound to be many problems to be solved in analyzing the therapeutic effects of drugs. To use this method in drug discovery, it is necessary to change the traditional mode and establish a brand-new drug discovery strategy. The main problems that need to be solved are the evaluation of activity, the correlation between the screening model and the disease, the possible factors that affect the screening model, the systematic evaluation of the drug action, etc.

2.2 Directed screening

The application of combinatorial chemistry technology has brought about tremendous changes in the structure optimization and transformation of active compounds and greatly improved the efficiency. For the lead compounds discovered in the high-throughput screening process, structural optimization and modification are important measures for the discovery of high-quality drugs. According to the law of drug discovery, the more new compounds are optimized or modified, the higher the quality of the drug, so combinatorial chemistry greatly promotes this process.

2.3 Approach to molecular design

There are two main ways of applying computer-aided drug design (CADD) in the discovery process of new drugs. The first method is to establish a three-dimensional active site structure by simulating the structure of the drug target, and then design the molecular structure of the compound that can be combined with the active site, and at last use a synthetic method to obtain the compound. The second method, computer screening, emerged after years of development. This method is based on the active compound or the effective medicinal chemical structure that is already known, referring to the structural characteristics of the drug target, and then performing activity screening after obtaining the compound by synthetic means. The purpose of this method is to obtain drugs with better effects.

3 Problems and prospects of high-throughput drug screening technology in new drug discovery


High-throughput screening technology has attracted the attention of universal drug research institutions due to its rapid, sensitive, and highly specific advantages. As a method of drug screening, HTS still has limitations. Firstly, it mainly uses in vitro experimental models at the molecular and cellular levels. Therefore, any models used in the process cannot fully reflect the overall pharmacological effects of the drug. Secondly, the models used for HTS are limited and constantly evolving. It is also unrealistic to establish an ideal model that reflects all the physiological functions of human body or the effects of drugs on the entire body.


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