Phenotypic and target-based HTS in drug discovery

Expert-driven In Silico Drug Discovery Solutions
8 December 2022
Svitlana Kondovych
Senior Researcher

When starting the search for a new drug amid thousands of available compounds, an immediate question of the proper and most advantageous screening approach arises. Among the traditionally established, reliable, and best-performing screening strategies, phenotypic and target-based approaches rank at the top, defining the two biggest directions in high-throughput screening (HTS) [1-3]. Both approaches possess their particular advantages but also face a number of shortcomings and challenges, hence the choice of the screening method depends on a specific drug development research task [1, 4].

The former approach, phenotypic screening, relies on the direct observation of the desired drug effect in cells, tissues, or animals, due to altering a cell phenotype by a drug candidate. Within this strategy, only molecules with relevant solubility and cell permeability pass the screening and produce good hit compounds for further optimization. At the same time, the specific mechanism of drug-target interaction, as well as the identity of the target, can in principle remain unknown – for instance, due to the complexity of the disease process, signaling cascade, or lack of corresponding studies. These benefits make phenotypic screening favorable for discovering and testing first-generation medications. Being a traditional approach with a long history, it nevertheless continues to show high performance and efficiency in drug discovery [5]. However, this method is associated with a few challenges that can hinder its usage in HTS, such as significant cost and time consumption, limited availability of cells, and complicated methodologies. These drawbacks have forced research and industrial communities to search for a new screening paradigm, which resulted in target-based screening approaches, widely adopted nowadays.

Figure 1. Advantages of phenotypic and target-based screening approaches

With respect to advanced target-based screening techniques, they have become the golden standard in HTS drug discovery, as they allow a fast and efficient simultaneous check of large compound sets. In the frame of this approach, extensive compound libraries are screened for favorable interactions – ‘hits’ – with a target molecule involved in a disease process. A hit event means the immediate detection of a drug candidate with the desired activity. This strategy not only accelerated the identification of novel drugs but also opened the route to the improvement of existing medications and the development of new generation treatments against well-studied diseases. Once the drug target is known, the challenges of phenotypic screening can be overcome: the target-based approach is less costly, relatively simple, and easy to implement. However, the desired in vivo properties of a detected compound are not guaranteed and usually require further investigation or even advanced correction by various biochemical methods [2,5].

In effect, according to up-to-date trends, the most beneficial strategy to advance small-molecule drug discovery may appear to involve the combination of both approaches [4, 6, 7]. Indeed, additional phenotypic screening of a targeted compound library will narrow the set of molecules to those readily active at the cellular level, thus possessing high solubility and permeability. As a matter of fact, the subsequent targeted screening of the highly soluble and permeable cell-based selected compounds additionally checked for unexpected activity or toxicity will improve the drug design workflow. Moreover, the phenotypic approach makes a good starting point for the identification of new molecular targets in cases when the disease mechanism is not fully understood or is associated with considerable biological complexity [8].

Given the complementary benefits and capabilities of the two screening methods, Life Chemicals considers both approaches for creating the most diverse and balanced collection of screening libraries and compound sets. We offer a broad variety of over 100 Targeted and Focused Screening Libraries with demonstrated or predicted activity towards various targets of interest, as well as several Pre-plated Focused Libraries designed for the identification of hit compounds via high-throughput/high-content screening. Moreover, Life Chemicals provides a comprehensive spectrum of Computational Chemistry services for the computer-aided design of molecules against any specific target, as well as Custom Synthesis for custom-targeted libraries and hit optimization.

Following the phenotypic route, Phenotypic Screening Libraries, comprising a total of 18,500 compounds, were created to include ChemDiversity and BioDiversity Phenotypic Sets.

Additionally, exclusive Pre-plated Diversity Sets composed of 50,000 novel screening compounds with high chemical and biological diversity and optimal physicochemical properties have been designed to find their successful application in both phenotypic and target-based HTS (Fig. 2).

Also, available are other screening compound libraries focused on structurally-diverse and drug-like compounds:

Please, contact us at for any additional information and price quotations.

Visit our Website for a detailed product description.

Download SD files with compound structures directly from our Downloads section

Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.

Figure 2. Examples of final compounds in the Pre-plated Diversity Set and their relation to the corresponding initial scaffolds and building blocks


  1. Blay, V., Tolani, B., Ho, S. P., Arkin, M. R. (2020). High-Throughput Screening: today’s biochemical and cell-based approaches. Drug Discovery Today, 25(10): 1807-1821 doi:10.1016/j.drudis.2020.07.024
  2. Croston G.E. (2017) The utility of target-based discovery, Expert Opinion on Drug Discovery, 12:5, 427-429, DOI: 10.1080/17460441.2017.1308351
  3. Moffat J.G., Vincent F., Lee J.A., Eder J., Prunotto M. (2017) Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat Rev Drug Discov. 16(8):531-543. doi:10.1038/nrd.2017.111
  4. Wassermann A.M., Camargo L.M., Auld D.S. (2014). Composition and applications of focus libraries to phenotypic assays. Front Pharmacol. 24; 5:164. DOI: 10.3389/fphar.2014.00164
  5. Swinney, D. C. (2013). Phenotypic vs. Target-Based Drug Discovery for First-in-Class Medicines. Clinical Pharmacology & Therapeutics, 93(4), 299-301. doi:10.1038/clpt.2012.236
  6. Heilker, R., Lessel, U., Bischoff, D. (2018). The power of combining phenotypic and target-focused drug discovery. Drug Discovery Today, 24(2):526-532, doi:10.1016/j.drudis.2018.10.009
  7. Moffat J.G., Rudolph J., Bailey D. (2014). Phenotypic screening in cancer drug discovery — past, present, and future. Nat Rev Drug Discov. 13(8):588-602. doi:10.1038/nrd4366
  8. Lee J, Bogyo M. (2013). Target deconvolution techniques in modern phenotypic profiling. Curr Opin Chem Biol. 17(1):118-26. doi: 10.1016/j.cbpa.2012.12.022
8 December 2022, 17:08 Svitlana Kondovych Computational Chemistry

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