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Introductory Chapter: High-Throughput Screening - A New Tool for Precision Medicine

Written By

Shailendra K. Saxena, Vimal K. Maurya, Saniya Ansari, Swatantra Kumar, Shivani Maurya, Ankur Gupta, Anil K. Tripathi and Bipin Puri

Submitted: 07 February 2022 Published: 25 May 2022

DOI: 10.5772/intechopen.104456

From the Edited Volume

High-Throughput Screening for Drug Discovery

Edited by Shailendra K. Saxena

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1. Introduction

High-Throughput Screening (HTS) is a programmed process that can rapidly identify active compounds (chemical /biological), antibodies, genes, or one or more candidates based on specific criteria [1]. In the pharmaceutical industry, HTS has been applied for novel drug discovery to overcome the conventional “trial and error” strategies to discover new therapeutic targets or validate their biological effects. Thus, a large number of biological effectors and modulators can be screened against specific targets in a short period using HTS technology during humanitarian emergencies [2]. HTS can also be used to evaluate pharmacological targets and pharmacological profile of agonists and antagonists for various receptors such as G-protein-coupled receptors (GPCRs) and enzymes. In recent years, a large number of drugs in clinical trials have come through HTS campaigns, establishing HTS as a reliable hit-finding technique. HTS has recently emerged as one of the important methods in the area of drug and vaccine design [3, 4, 5, 6]. It also allows the immediate incorporation of broad screening collections such as GPCR, kinase, and ion channel-based libraries, as well as the use of client-supplied libraries, into an HTS campaign [7]. Over the past decades, HTS mainly focused on several fundamental technologies like homogeneous assays, high-density microplates, high-performance microliter dispensers, imaging, laboratory automation, and combinatorial chemistry and genomics [8]. The success of HTS is dependent on the identification of meaningful assay systems. HTS is mainly performed using in silico methods (ligand-based drug design and structure-based drug design) in vitro methods (cell-based assays and biochemical assays), in-vivo methods (whole organism-based assays) [9].

Recently, with a rising need to store, access, and compute more sequencing reads and other biological data, HTS technology is becoming more important in the therapeutic context [10]. High-throughput biochemical measures of new variation, thorough health records, and open data sharing will improve our capacity to read individual genomics and understand exactly human health and diseases. The availability of HTS has surpassed current procedures for reporting on data analysis techniques. Lower prices and better accessibility led to an influx of data and related studies, which helped to progress bioinformatics. Innovative, dependable, and accurate omics-based study (i.e., genomics, transcriptomics, and proteomics) would aid novel drug development and precision medicine research [11].

This book also provides an in-depth look at the technologies utilized to detect biological reactions in HTS bioassays, such as fluorescence, luminescence, and atomic absorbance. In the context of anti-infective drug design, discovery, and development, the applications of HTS, reverse pharmacology, present obstacles, and future views of HTS in the pharmaceutical and biotechnology industries are explored. In this book, we describe a novel, multiplex immuno-assay platform based on high-throughput flow cytometry technology and advanced computational algorithms for data analysis. The assay simultaneously measures T cell dynamics including phenotype, time-dependent expression of activation markers, secreted effector cytokines, and proliferation. Further, this book covers the recent advances that use high-throughput methods to move towards the generation of a comprehensive network of extracellular protein-protein interactions (ePPIs) in humans for future targeted drug discovery. Furthermore, the book focuses on the advancement of technologies in HTS methods and research advances in three major technology areas including miniaturization, automation and robotics, and artificial intelligence, which promises to help speed up the discovery of medicines and their development process. At last, this book provides comprehensive knowledge about the use of various machine-learning algorithms for the screening of Aryl hydrocarbon receptor (AhR) modulators that have minimum errors compared with structure-based methods.

Precision medicine has gained a lot of attention in recent years due to its unique approach i.e., “to target the right treatments to the right patients at the right time”. According to the National Institutes of Health (NIH), precision medicine is a new therapy and preventative strategy based on knowledge about an individual’s genes, environment, and lifestyle [12, 13]. Precision medicine aims to give accurate and personalized treatment to patients by using genomes, proteomics, and other related technologies to evaluate and identify biomarkers in huge sample groups for specific diseases [14]. Precision medicine attempts to limit medical expenses while achieving an optimal treatment impact by bringing humanism, ethics, economics, sociology, and other knowledge factors together [15]. Precision medicine is a new medical concept for gaining a comprehensive knowledge of a patient’s genetic and genomic data to estimate disease and make better preventive, diagnostic, and treatment decisions [16]. Medical oncology has progressed through three stages: cytotoxic chemical treatment, gene-driven precision medicine, and personalized molecule-targeted treatment (Figure 1) [17]. Precision medicine has entered a new phase in clinical practice today. Its overall purpose is to minimize mortality, morbidity, and disability from serious diseases, improve healthcare service quality (Table 1) [18, 19].

Figure 1.

Applications of precision medicine in cancer management, therapeutic drug monitoring, drug discovery and delivery.

AreaBiomarkersTreatmentDisease
Infectious diseasesCD4 + T cells, HIV viral loadHighly active antiretroviral therapyHIV/AIDS
CancerBCR-ABL1Blinatumomab, Bosutinib, Busulfan, Imatinib, NilotinibCML
EML4-ALKCrizotinib, Brigatinib, AlectinibLung cancer
Cardiovascular diseaseCYP2C19Citalopram, Clobazam, Doxepin, Clopidogrel, CarisoprodolCoronary artery disease (CAD)
Pulmonary diseaseG551DIvacaftorCystic fibrosis
Endocrine diseaseRETProphylactic thyroidectomy, CarbozantinibMultiple endocrine neoplasia type 2
HematologyFactor V LeidenAvoid prothrombotic drugsThrombosis
Hepatitis C viral loadDirect-acting antiviral agentsHepatitis C
Metabolic diseaseLDL cholesterolStatinsHyperlipidemia
NeurologyCXCL13ImmunotherapyAutoimmune encephalitis
PsychiatryGRIK1TopiramateAlcohol use disorder
Renal diseaseUrinary gene signatureAntirejection drugsTransplant rejection
OphthalmologyRPE65Gene therapyLeber’s congenital amaurosis
PharmacogenomicsCYP2A6VareniclineSmoking cessation

Table 1.

Examples of precision medicine applications for the management of various clinical conditions.

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2. Applications of high throughput screening (HTS) in precision medicine

Improvements in sequencing technology over the last 10 years have allowed several high-throughput sequencing platforms to provide novel insights to design personalized medicine [20]. Modern sequencing technology (Ion, Illumina, Torrent, Oxford Nanopore Technologies, pacific biosciences, etc.) created new paths for HTS in the area of medicine. Epigenetic applications, Genomic (DNA-seq), and transcriptomic (RNA-seq), are all part of HTS. To determine genomic variants (insertion or deletion, single nucleotide variants, copy number alterations, and fundamental changes) from biological samples, whole-genome sequencing (WGS), and whole-exome sequencing (WES) is used (Figure 2) [21, 22]. Identification of new transcripts, characterization of gene expression profiles, alternative splicing, RNA editing, and fusion transcripts are all feasible using RNA-seq. [23]. Similarly, next-generation sequencing (NGS) may quickly identify or “sequence” huge parts of a person’s genome and are significant advancements in precision medicine clinical applications. These tests can assist patients, doctors, and researchers uncover genetic variations that can help them diagnose, treat, and know more about human disease. Apart from this, NGS techniques can also be applied in the area of metagenomics, RNAseq, ribosome profiling, targeted sequencing, and minor variant reconstruction, as well as a wide range of post-pipeline studies that combine genomic, clinical, epidemiological, and ecological data [24, 25].

Figure 2.

Scheme for the high-throughput screening based development of personalized/precision medicine. Samples collected from the patients are subjected to DNA isolation and sequencing (NGS) for pharmacogenomics. Based on the analysis of sequencing (NGS) data, high-throughput screening (HTS) of the compound library is performed to identify the drug(s) of choice. Patient treatment with these drug(s) is monitored for its therapeutic and ADME profile. Based on the therapeutic effect of the drug(s), multi-population genome-wide association studies (GWAS) study may lead to development of personalized/precision medicine.

HTS has mostly been applied to specific areas of the genome or in the context of identifying microscopic pathogens. Prenatal assays intended to identify chromosomal abnormalities in cell-free DNA from maternal blood are clinically accessible [26]. Targeted HTS of clinically actionable mutations is also being used to guide illness diagnosis and therapy [27]. HTS has also been used in clinical settings to track pathogen outbreaks like methicillin-resistant Staphylococcus aureus infections. The development and usage of these specialized assays will continue to grow, but precision medicine depends on the potential therapeutic use of more extensive methods like WGS, which is still facing complications. WGS is the most comprehensive technique for potential therapeutic use since that marks the next stage in the path to a complete understanding of the genetic determinants of a patient’s heritable character [28]. Additional genome sequencing, and data from large-scale genomics efforts like ENCODE and GTEx, which allow the development of even more extensive datasets, will help interpret the variations. Community resources for correlating phenotypes to sequences will be provided through open access programs including the Personal Genomes Project and integrated Personal Omics Profiling [29].

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3. Few prime areas of high throughput screening (HTS) for precision medicine

3.1 Management of infectious diseases

Efforts have recently been made to combine these technologies with bioinformatics and epidemiology to improve public health surveillance, investigations, and control of infectious diseases [30]. The previous 40 years had a substantial influence on the knowledge of infectious diseases. A broad spectrum of medically important viruses, bacteria, parasites, fungus, and other pathogens have been studied using next-generation sequencing [31]. Many of these pathogens are directly important to the development and assessment of vaccinations, medicines, infection control, and a variety of nonmedical pandemic countermeasures [32].

3.2 Management of cancer

Recently HTS has been coupled with various sequencing techniques in the design of precision medicine for the treatment of various types of cancers like multiple myeloma, glioblastoma, and pediatric cancers. A wide range of FDA approved drugs such as temsirolimus (mTOR inhibitor), ceritinib (ALK inhibitor), and BI2536 (PLK1 inhibitor), panobinostat, bortezomib, ixazomib, carfilzomib, and selinexor, bortezomib (proteasome inhibitor), Bcl-2 inhibitor ABT-263 with the mTOR inhibitor AZD-8055 have been tested as precision therapy for multiple myeloma, glioblastoma, and pediatric cancer [33, 34, 35].

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4. Conclusions

In clinical and preclinical research, there have been a few attempts to integrate throughput screening technologies with precision medicine. The relevance of high-throughput screening approaches in identifying and designing precision therapies for the treatment of various diseases is highlighted in this chapter. Over the last ten years, advances in sequencing technology have enabled several high-throughput sequencing platforms to bring unique insights into the creation of customized medicine. The sequencing technologies of the present day (Ion, Illumina, Torrent, Oxford Nanopore Technologies, pacific biosciences) created a new roadmap for HTS technologies to identify and design precision therapeutics.

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5. Future perspectives

The development of a single definition for precision medicine will aid transdisciplinary areas with a shared understanding of concepts and enhance collaborative ideas. Standardization of HTS and analytical methods will make it easier to validate and replicate findings in clinically relevant timeframes. This, along with interdisciplinary cooperation, will allow it to be fully integrated into patient care and treatment via the development of novel diagnostic, predictive, and prognostic tests. The creation of broad conceptual frameworks that address the underlying drivers of health across specialized areas will be facilitated by the establishment of a shared precision medicine definition, which will promote collaboration between the transdisciplinary domains that make up precision medicine. It may be beneficial to establish a set of recommendations in the next 5–10 years to assist in deciding whether or not research activities or therapies fit precision medicine requirements. These principles might determine if the endeavor should include efforts to personalize therapies, a focus on genetics/biology, the environment, nutrition, and/or lifestyle, as well as the amount to which these distinct variables interact.

References

  1. 1. Szymański P, Markowicz M, Mikiciuk-Olasik E. Adaptation of high-throughput screening in drug discovery-toxicological screening tests. International Journal of Molecular Sciences. 2012;13(1):427-452. DOI: 10.3390/ijms13010427
  2. 2. Sachinidis A. High-throughput base editing: A promising technology for precision medicine and drug discovery. Signal Transduction and Targeted Therapy. 2021;6(1):221. DOI: 10.1038/s41392-021-00633-0
  3. 3. Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. VirusDisease. 2020;31(2):179-193. DOI: 10.1007/s13337-020-00598-8
  4. 4. Maurya VK, Kumar S, Bhatt MLB, Saxena SK. Antiviral activity of traditional medicinal plants from Ayurveda against SARS-CoV-2 infection. Journal of Biomolecular Structure and Dynamics. 2022;40(4):1719-1735. DOI: 10.1080/07391102.2020.1832577
  5. 5. Mishra S, Maurya VK, Kumar S, Ankita KA, Saxena SK. Clinical management and therapeutic strategies for the thyroid-associated Ophthalmopathy: Current and future perspectives. Current Eye Research. 2020;45(11):1325-1341. DOI: 10.1080/02713683.2020.1776331
  6. 6. Kumar S, Maurya VK, Prasad AK, Bhatt MLB, Saxena SK. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). VirusDisease. 2020;31(1):13-21. DOI: 10.1007/s13337-020-00571-5
  7. 7. Aldewachi H, Al-Zidan RN, Conner MT, Salman MM. High-throughput screening platforms in the discovery of novel drugs for neurodegenerative diseases. Bioengineering (Basel). 2021;8(2):30. DOI: 10.3390/bioengineering8020030
  8. 8. Shinn P, Chen L, Ferrer M, et al. High-throughput screening for drug combinations. Methods in Molecular Biology. 2019;1939:11-35. DOI: 10.1007/978-1-4939-9089-4_2
  9. 9. Gorshkov K, Chen CZ, Marshall RE, et al. Advancing precision medicine with personalized drug screening. Drug Discovery Today. 2019;24(1):272-278. DOI: 10.1016/j.drudis.2018.08.010
  10. 10. Trombetta RP, Dunman PM, Schwarz EM, Kates SL, Awad HA. A high-throughput screening approach to repurpose FDA-approved drugs for bactericidal applications against staphylococcus aureus small-colony variants. mSphere. 2018;3(5):e00422-e00418. DOI: 10.1128/mSphere.00422-18
  11. 11. Williams JR, Lorenzo D, Salerno J, Yeh VM, Mitrani VB, Kripalani S. Current applications of precision medicine: A bibliometric analysis. Personalized Medicine. 2019;16(4):351-359. DOI: 10.2217/pme-2018-0089
  12. 12. Manzari MT, Shamay Y, Kiguchi H, Rosen N, Scaltriti M, Heller DA. Targeted drug delivery strategies for precision medicines. Nature Reviews Materials. 2021;6(4):351-370. DOI: 10.1038/s41578-020-00269-6
  13. 13. Collins H, Calvo S, Greenberg K, Forman Neall L, Morrison S. Information needs in the precision medicine era: How genetics home reference can help. Interactive Journal of Medical Research. 2016;5(2):e13. DOI: 10.2196/ijmr.5199
  14. 14. Lightbody G, Haberland V, Browne F, et al. Review of applications of high-throughput sequencing in personalized medicine: Barriers and facilitators of future progress in research and clinical application. Briefings in Bioinformatics. 2019;20(5):1795-1811. DOI: 10.1093/bib/bby051
  15. 15. Alterovitz G, Dean D, Goble C, et al. Enabling precision medicine via standard communication of HTS provenance, analysis, and results. PLoS Biology. 2018;16(12):e3000099. DOI: 10.1371/journal.pbio.3000099
  16. 16. Jameson JL, Longo DL. Precision medicine—Personalized, problematic, and promising. The New England Journal of Medicine. 2015;372(23):2229-2234. DOI: 10.1056/NEJMsb1503104
  17. 17. Phan N, Hong JJ, Tofig B, et al. A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumororganoids. Communications Biology. 2019;2:78. DOI: 10.1038/s42003-019-0305-x
  18. 18. Wang ZG, Zhang L, Zhao WJ. Definition and application of precision medicine. Chinese Journal of Traumatology. 2016;19(5):249-250. DOI: 10.1016/j.cjtee.2016.04.005
  19. 19. Hasanzad M, Sarhangi N, AghaeiMeybodi HR, Nikfar S, Khatami F, Larijani B. Precision medicine in non communicable diseases. International Journal of Molecular and Cellular Medicine. 2019;8(Suppl1):1-18. DOI: 10.22088/IJMCM.BUMS.8.2.1
  20. 20. Wang C, Xu P, Zhang L, Huang J, Zhu K, Luo C. Current strategies and applications for precision drug design. Frontiers in Pharmacology. 2018;9:787. DOI: 10.3389/fphar.2018.00787
  21. 21. Taylor JY, Barcelona de Mendoza V. Improving -omics-based research and precision health in minority populations: Recommendations for nurse scientists. Journal of Nursing Scholarship. 2018;50(1):11-19. DOI: 10.1111/jnu.12358
  22. 22. Chen R, Mias GI, Li-Pook-Than J, et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell. 2012;148(6):1293-1307. DOI: 10.1016/j.cell.2012.02.009
  23. 23. Rehm HL. Disease-targeted sequencing: A cornerstone in the clinic. Nature Reviews. Genetics. 2013;14(4):295-300. DOI: 10.1038/nrg3463
  24. 24. Shyr D, Liu Q. Next generation sequencing in cancer research and clinical application. Biological Procedures Online. 2013;15(1):4. DOI: 10.1186/1480-9222-15-4
  25. 25. Reuter JA, Spacek DV, Snyder MP. High-throughput sequencing technologies. Molecular Cell. 2015;58(4):586-597. DOI: 10.1016/j.molcel.2015.05.004
  26. 26. Nussinov R, Jang H, Tsai CJ, Cheng F. Correction: Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers. PLoSComputational Biology. 2019;15(6):e1007114. DOI: 10.1371/journal.pcbi.1007114
  27. 27. Zhu S, Rooney S, Michlewski G. RNA-targeted therapies and high-throughput screening methods. International Journal of Molecular Sciences. 2020;21(8):2996. DOI: 10.3390/ijms21082996
  28. 28. Azarian T, Cook RL, Johnson JA, et al. Whole-genome sequencing for outbreak investigations of methicillin-resistant Staphylococcus aureus in the neonatal intensive care unit: Time for routine practice? Infection Control and Hospital Epidemiology. 2015;36(7):777-785. DOI: 10.1017/ice.2015.73
  29. 29. Putignani L, Gasbarrini A, Dallapiccola B. Potential of multiomics technology in precision medicine. Current Opinion in Gastroenterology. 2019;35(6):491-498. DOI: 10.1097/MOG.0000000000000589
  30. 30. Centers for disease control and prevention (CDC). Infectious Diseases: Precision Medicine for Public Health. 2022. https://blogs.cdc.gov/genomics/2015/09/24/infectious-diseases/ [Accessed: January 30, 2022]
  31. 31. Lange C, Aarnoutse R, Chesov D, et al. Perspective for precision medicine for tuberculosis. Frontiers in Immunology. 2020;11:566608. DOI: 10.3389/fimmu.2020.566608
  32. 32. Leguia M, Vila-Sanjurjo A, Chain PSG, Berry IM, Jarman RG, Pollett S. Precision medicine and precision public health in the era of pathogen next-generation sequencing. The Journal of Infectious Diseases. 2020;221(Suppl 3):S289-S291. DOI: 10.1093/infdis/jiz424
  33. 33. Coffey DG, Cowan AJ, DeGraaff B, et al. High-throughput drug screening and multi-omic analysis to guide individualized treatment for multiple myeloma. JCO Precision Oncology. 2021;5:PO.20.00442. DOI: 10.1200/PO.20.00442
  34. 34. Quartararo CE, Reznik E, deCarvalho AC, Mikkelsen T, Stockwell BR. High-throughput screening of patient-derived cultures reveals potential for precision medicine in glioblastoma. ACS Medical Chemistry Letters. 2015;6(8):948-952. DOI: 10.1021/acsmedchemlett.5b00128
  35. 35. Tsoli M, Wadham C, Pinese M, et al. Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer. Cancer Biology and Therapy. 2018;19(12):1078-1087. DOI: 10.1080/15384047.2018.1491498

Written By

Shailendra K. Saxena, Vimal K. Maurya, Saniya Ansari, Swatantra Kumar, Shivani Maurya, Ankur Gupta, Anil K. Tripathi and Bipin Puri

Submitted: 07 February 2022 Published: 25 May 2022