Impact of High Throughput Screening in Biomedical Research

I. INTRODUCTION:

Screening is an important step in any research and technologies used to apply this step are continuing to improve, in order to minimize any obstacle and until reaching the most benefits from their use. In the 1990s High throughput screening method was developed and continued to evolve. Nowadays HTS is one of the modern screening methods which is applied in different research fields such as biomedical researches, drug discovery, genomics and biotechnology. HTS is mainly a robotic system which is performed in either 384, 1536, or 3456 wells microtitre plates, for the aim of hit identification (active molecules) in an in vitro assay.

This allows researchers to screen a huge number of molecules in a robust manner.

Pharmaceutical industries always seek for the development of their drug discovery process in order to increase their income and to get patency from novel drugs, therefore they started to focus on using HTS on their experiments to give them more rapid and efficient hit identification and lead optimization from their chemical libraries. Statistics show that when HTS was applied in industries that work on natural products, it yields a huge number of hits, making these industries become innovative and increasing their productivity. 

Thus, pharmaceutical companies have established HTS facilities only for their workers and experts to increase their benefits from the HTS impact in drug discovery. On the other hand, academia uses HTS to support their research and to better understand the biological basis of novel therapeutic targets. However, to establish HTS centers in academia, they require knowledge, funding, and experts which can’t be easily accessed, also HTS facilities in academia serve as training centers for students and scientists. 

Therefore, various gaps were found between applying HTS drug discovery facilities in pharmaceutical industries and in academia. Hence, to bridge those gaps, different pharmaceutical industries tried to collaborate with academia through funding or expertise in order to improve the innovation for both. One example of this collaboration is the budget offered by the Scottish Universities Life Sciences Alliance (SULSA) to establish a HTS center in academia for the purpose of increasing the quality, knowledge, and experience offered by this center. Also, the Congress offers funding for the national cancer institute (NCI) to support laboratory researches. Thus the benefits from HTS implementation was achieved in both pharmaceutical industry and academia..

II. LITERATURE REVIEW:

The high throughput screening method was discussed in various literature, showing its benefits, techniques of handling and successful applications. Herein, brief examples of HTS centers and successful applications of HTS in drug discovery and biomedical research:

Examples of HTS centers:

The Institute for Chemistry and Cell Biology (ICCB) contains HTS labs which are the first labs used in academia. The aim of these HTS labs is chemical genetics as they are used to identify the novel small molecules and connect them with the biological target pathway.

In 2002, HTS lab was established at the Center for Aging, Genetics, and Neurodegeneration (CAGN) in order to aid the researchers to be conducted in cell-free and cell-based assays, also to screen for novel therapeutics among their small molecule libraries for treatment of neurodegenerative disorders.

Example of the impact of HTS in biomedical research:

In cancer therapy, resistance usually happens to chemotherapy, which makes researchers try to find another way to solve this problem. Combinatorial HTS (cHTS) was used to solve this issue by identifying and evaluating the effect of unique genotype selective combination therapy, on resistant BRAF or RAS-mutated melanoma cells. As a result of the use of cHTS, new combination therapies were found that were able to overcome melanoma resistant cells, such as statins and cyclin-dependent kinase inhibitor combination regimen.

Examples of successful drug discovery using HTS:

The University of Michigan has HTS labs which are involved in different researches and assist the university to publish around 52 articles with 15 patent articles. Amlexanox, the miracle drug that was previously discovered to treat aphthous, asthma and allergic rhinitis. During the drug repurposing experiments using HTS, which was done at the University of Michigan, Amlexanox was found to selectively inhibit IKK-? and TBK1 which are protein kinases that have a role in obesity and insulin resistance), therefore, HTS showed an important effect in discovering Amlexanox as novel drug for treating type 2 diabetes.

HTS has shown an evolution in hepatitis C treatment also, as it was used to discover compounds that inhibit hepatitis C NS5A replication. Interestingly, it succeeded in discovering BMS?858 (screening hit) and BMS?790052 (clinical candidate) inhibitors of hepatitis C virus (HCV) NS5A, which were involved in further lead optimization.

In 1997, Pfizer used HTS to screen a library of compounds in order to find Chemokine receptor antagonists to inhibit the entry of the virus inside the human cell. Consequently, in 2007 the FDA had approved Maraviroc (Selzentry/Celsentri) for the treatment of HIV as a successful example of the power of HTS.

In the past, it was thought that discovering a cytokine agonist is something impossible, however, HTS now makes this discovery is accessible. In 2008, the FDA had approved a new drug for the treatment of chronic idiopathic thrombocytopenic purpura, this drug was eltrombopag (Promacta/Revolade; GlaxoSmithKline), which stimulates thrombopoietin receptor through an allosteric binding site, resembling another successful example of the benefits of HTS in drug discovery.

III. DISCUSSION:

The high throughput screening method becomes the most robust, automatic and an applicable screening tool that resembles an entry point to the drug discovery process. HTS allows researchers to rapidly screen a huge number of molecules and simply identifying the hits of fairly low concentration, high quality, and high specificity. Furthermore, HTS decreases the errors happen from human handling techniques. It is thought that the more the HTS is applied in scientific researches the shorter the time is consumed by a target to lead identification process. In literature, the drug discovery process is done in several steps which take around 1-3 years, while using HTS make screening occurs in 1 week to 1-3 months only, therefore one of the benefits of HTS is ‘saving time’. 

In addition to saving time, HTS contributes to the intellectual innovation of drug design and drug discovery, allowing more therapeutics to reach the market. Screening always based on random searching, which leads to many faults, but when HTS is applied, it moves to search to become more rapid focus screening with minimum faults. Different scientific techniques such as chemogenomics, RNA interference (RNAi) screening, crystallography, and eADMET, get benefits from using HTS technologies in their techniques. Besides to HTS benefits, biomedical researchers may face obstacles from using HTS, such as the need for experience and funding. Active hits resulted from HTS use, are not always suitable to be drugs as their quality is low, further optimization and removing art-factual compounds are needed in order to improve the quality of hits and to be applicable in medicinal chemistry. 

In addition to poor quality hits, several compounds may give false positive results (inactive molecules that score as hits in the testing) and odd dose-response curve while using HTS, which make researchers follow these false positive results aiming to give them novel therapeutics. After consuming time and money for separating and analyzing the false positives, researchers finally have recognized that these false positive results are useless and sometimes are inactive, thus hindering researchers from using HTS in their experiments. Further experiments were done in order to solve the false positive problem until they discover a tool that analyzes the hits and highlight or remove any false positives either physically or electronically, this tool is called PAINS (pan assay interference compounds), which was successful in solving this obstacle. Therefore, the benefits gathered from using HTS as a screening tool in biomedical research outweigh the limitations observed from its use and by increasing science and researches, these limitations could be handled.

IV. CONCLUSION:

HTS is a modern screening technology that is used widely in pharmaceutical industries to improve the creativity and facilitate the drug discovery process, also HTS has a great impact in academia and biomedical researches where it produces successful results and sometimes novel therapeutics. Despite HTS benefits, its implementation may face some limitations, but these limitations can be minimized through further development in this method. In the future, it is predicted that HTS will be more sophisticated, reproducible, quality and flexible technology, with minimum false positive results. Awareness should be taken on the proper criteria for selecting the most appropriate screening strategy in lead finding process, which increases the successful implementation of high throughput screening.

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