High Throughput Screening in Modern Research

I. Introduction: Broadening the Horizon of Drug Discovery

In the realm of scientific research, the screening process is a fundamental step that has seen significant advancements over recent decades. High throughput screening (HTS), a method that emerged in the 1990s, exemplifies these advancements. This technology is continually evolving, driven by the quest to overcome obstacles and maximize the benefits it offers. Today, HTS stands as a cornerstone in various fields, including biomedical research, drug discovery, genomics, and biotechnology. At its core, HTS involves the use of sophisticated robotic systems to conduct experiments in microtitre plates, typically with 384, 1536, or 3456 wells.

This high-tech approach facilitates the identification of active molecules or 'hits' in an in vitro assay, allowing researchers to screen a vast array of molecules efficiently and robustly.

In the pharmaceutical industry, the pressure to innovate and enhance the drug discovery process is immense. Companies are driven by the potential financial rewards and the prestige of developing novel drugs that receive patents. Consequently, HTS has become integral to pharmaceutical research, providing a more rapid and efficient means of hit identification and lead optimization from expansive chemical libraries. Data indicates that industries utilizing HTS, particularly those focused on natural products, have experienced a surge in the number of hits identified, fostering innovation and boosting productivity.

To capitalize on the advantages of HTS, many pharmaceutical companies have established dedicated HTS facilities, accessible exclusively to their employees and experts. This strategic move aims to harness the full potential of HTS in drug discovery. Conversely, academic institutions leverage HTS to advance their research and deepen their understanding of the biological underpinnings of novel therapeutic targets. However, setting up HTS centers in academia presents challenges, including the need for expertise, funding, and knowledge, which are not easily accessible. Nonetheless, these facilities serve as invaluable training grounds for students and scientists, nurturing the next generation of researchers.

Despite the evident benefits of HTS, a gap persists between its application in pharmaceutical industries and academia. Bridging this divide has led to collaborations, where pharmaceutical industries partner with academia, offering funding or expertise to spur innovation. A notable example is the initiative by the Scottish Universities Life Sciences Alliance (SULSA), which provided funding for the establishment of an HTS center in academia. This initiative aimed to enhance the quality, knowledge, and experience offered by the center. Similarly, Congress has allocated funds to the National Cancer Institute (NCI) to support laboratory research, underscoring the mutual benefits achieved through HTS implementation in both the pharmaceutical industry and academia.

II. Literature Review: Unveiling the Impact of HTS

The high throughput screening method has been extensively discussed in literature, highlighting its numerous benefits, handling techniques, and successful applications. This section provides a glimpse into HTS centers and the successful applications of HTS in drug discovery and biomedical research.

Examples of HTS Centers and Their Contributions

The Institute for Chemistry and Cell Biology (ICCB) holds the distinction of housing the first HTS labs within an academic setting. These labs are dedicated to chemical genetics, aiming to identify novel small molecules and establish connections with biological target pathways. Similarly, in 2002, an HTS lab was established at the Center for Aging, Genetics, and Neurodegeneration (CAGN) to assist researchers in conducting cell-free and cell-based assays. This lab also screens small molecule libraries for novel therapeutics targeting neurodegenerative disorders.

Impact of HTS in Biomedical Research: A Case Study in Cancer Therapy

Cancer therapy often encounters the challenge of resistance to chemotherapy, prompting researchers to explore alternative solutions. Combinatorial HTS (cHTS) emerged as a promising approach to address this issue by identifying and evaluating genotype-specific combination therapies for resistant BRAF or RAS-mutated melanoma cells. Through cHTS, researchers discovered novel combination therapies capable of overcoming melanoma resistance, exemplified by the combination of statins and cyclin-dependent kinase inhibitors. This breakthrough underscores the transformative potential of HTS in reshaping cancer treatment paradigms.

Successful Drug Discovery Through HTS: Pioneering Examples

The University of Michigan's HTS labs have played a pivotal role in diverse research endeavors, resulting in the publication of approximately 52 articles, including 15 patents. A standout achievement is the repurposing of Amlexanox, a drug initially discovered for treating aphthous, asthma, and allergic rhinitis. Through HTS-driven experiments, Amlexanox was found to selectively inhibit IKK-? and TBK1, protein kinases implicated in obesity and insulin resistance. Consequently, HTS facilitated the identification of Amlexanox as a novel therapeutic for type 2 diabetes.

HTS has also catalyzed advancements in hepatitis C treatment by identifying compounds that inhibit hepatitis C NS5A replication. Notably, it led to the discovery of BMS?858 (screening hit) and BMS?790052 (clinical candidate), inhibitors of the hepatitis C virus (HCV) NS5A, which underwent further lead optimization.

In 1997, Pfizer harnessed HTS to screen a compound library in search of chemokine receptor antagonists, ultimately resulting in the FDA approval of Maraviroc (Selzentry/Celsentri) in 2007 for HIV treatment. This success highlights the profound impact of HTS on drug development.

In the past, discovering cytokine agonists was deemed implausible, yet HTS has made this possibility a reality. In 2008, the FDA approved eltrombopag (Promacta/Revolade; GlaxoSmithKline) for treating chronic idiopathic thrombocytopenic purpura. This drug stimulates the thrombopoietin receptor through an allosteric binding site, exemplifying another triumph of HTS in drug discovery.

III. Discussion: The Multifaceted Role of HTS

High throughput screening has become an indispensable tool in scientific research, revolutionizing the drug discovery process. HTS empowers researchers to swiftly screen vast numbers of molecules, identifying hits with remarkable precision and quality. This technology minimizes human errors, expediting the target-to-lead identification process. Traditional drug discovery, which typically spans 1-3 years, can be condensed to a mere 1 week to 1-3 months with HTS, making its most significant advantage the ability to save time.

Beyond time efficiency, HTS fuels intellectual innovation in drug design and discovery, facilitating the market entry of new therapeutics. Conventional screening methods often rely on random searches, prone to errors. In contrast, HTS offers a more focused and rapid screening approach with minimal faults. Various scientific techniques, including chemogenomics, RNA interference (RNAi) screening, crystallography, and eADMET, benefit from integrating HTS technologies into their methodologies.

However, the adoption of HTS in biomedical research is not without challenges. Researchers may encounter obstacles such as the need for expertise and funding. Moreover, active hits generated by HTS may not always meet the quality standards required for drug development, necessitating further optimization and the removal of artifactual compounds. Additionally, false positive results—inactive molecules erroneously identified as hits—pose a significant challenge. These false positives can lead researchers astray, consuming valuable resources. To address this issue, the development of tools like PAINS (pan assay interference compounds) has been instrumental in identifying and mitigating false positives, ensuring that the benefits of HTS outweigh its limitations.

IV. Conclusion of HTS

High throughput screening stands as a modern technological marvel, widely used in the pharmaceutical industry to drive creativity and streamline the drug discovery process. Its impact extends to academia and biomedical research, where it has yielded successful outcomes and occasionally unveiled novel therapeutics. Despite the undeniable benefits of HTS, its implementation may face limitations, including false positives and resource constraints. However, ongoing advancements in HTS technology hold the promise of minimizing these limitations. In the future, HTS is expected to evolve into a more sophisticated, reproducible, high-quality, and flexible technology with minimal false positives. Careful consideration of screening strategy criteria is crucial for successful HTS implementation, ensuring its continued role as a foundational tool in drug discovery.

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