Diversity-based Screening of Compound Libraries in Drug Discovery

Expert-driven In Silico Drug Discovery Solutions
28 January 2020
Andrew Golub
Group Leader, Molecular Design

It is generally recognized by medicinal chemists that the success of any screening campaign1, 2 depends on a number of most essential features of a screening library, such as:

  • Size (number of compounds)
  • Quality (structural attractiveness, synthetic feasibility3 and purity)
  • Physicochemical parameters (drug-likeness or lead-likeness)
  • Diversity (coverage of chemistry space4)

High-throughput screening (HTS) allowed rapid bioactivity profile exploration of large compound libraries5-8 with the aim to significantly raise the probability of identifying diverse hits for further investigation. For target classes with limited number of known active chemotypes or for phenotypic assays, structural diversity in screening libraries is strictly recommended, as this can increase the chances of detecting multiple promising scaffolds for further development a wide spectrum of assays.9,10 Although broadest chemical diversity of compound libraries is preferred to make your screening projects a success, at the same time, some analogs in the screening set are desired to enable SAR analysis and chemical optimization.

The diversity-based library design attempts to explore appropriate chemical space by optimizing biological relevance and compound diversity in order to provide multiple starting points for further hit/lead development (Fig. 1). Diversity of the library can be based on a number of characteristics that describe compounds in terms of structural and/or physicochemical properties, such as:

  • Molecular scaffolds
  • Chemical descriptors (fingerprint-based11, shape-based12, 13 or pharmacophore-based14)
  • Biological descriptors (affinity fingerprints15, 16, 17 or high-throughput screening fingerprint, HTS-FP18)

In contrast to diversity-based libraries (which are predominantly designed for targets with few known active chemotypes), there are screening libraries (named “focused libraries”) that are intended for well-studied targets, such as protein kinases, GPCRs, nuclear receptors etc. Using structure-based and/or ligand-based approach, focused libraries can be selected from larger diversity libraries to be enriched with active chemotypes. This type of libraries usually provides higher hit rates, however, may not effectively cover a diverse chemical space.

The diversity-based libraries are especially useful in phenotypic screening where particular attention is paid to physicochemical parameters of compounds to optimize their solubility and cell permeability.

Diversity screening flowchart example

Fig. 1. An example of diversity screening flowchart

Nowadays, common phenotypic assays employ cell proliferation or selective growth inhibition assays routinely applied in areas, such as oncology or infectious disease. Approaches applied to chemical library screening include a wide use of engineered cell lines in a reporter-gene assay, intracellular sensors or high content screening procedures19, 20. Normally, the predominant strategy for the assembly of a library for phenotypic screening is to select the most chemically diverse compound set on the basis of diversity measures, proceeding from specific characteristics described earlier in this article.

The rationale behind this was the belief that chemical diversity ultimately implies biological diversity and that a chemically diverse screening library should cover a broad spectrum of targets and molecular processes, and, hence, can be a suitable starting point for various drug discovery projects. However, given the widely accepted assumption in medicinal chemistry that not all parts of the chemical space are biologically active or relevant, strategies that directly integrate a known biology of compounds into a screening set have taken phenotypic screening to the next level. By maximizing the known biodiversity instead of the chemical diversity of screening collections, these methods have been made possible by a vast amount of data on small molecules bioactivity that has become available over the past decade. 

Considering a high demand for this type of product on the market, our Company has come up with its in-house Pre-plated Diversity Sets (Fig. 2). It is one of the best solutions that is intended for broad spectrum screening projects, such as multi-target screening, phenotypic screening or for probing drug targets with unknown or few known active chemotypes. 

It should be pointed out that, as compared to other vendors, our Pre-plated Diversity Sets are distinctly characterised by a highly efficient distribution of main physicochemical descriptors and molecular scaffolds.

Example of the key descriptors distribution within 50K Pre-plated Diversity Set by Life Chemicals

Fig. 2. Example of the key descriptors distribution within 50K Pre-plated Diversity Set by Life Chemicals

The compounds are already formatted in 96- and/or 384-well plates of various types and are ready-to-use in any robotic HTS platform.

For more information about the Life Chemicals Pre-plated Diversity Sets, please follow this link: https://lifechemicals.com/screening-libraries/pre-plated-diversity-sets

28 January 2020, 16:30 Andrew Golub Computational Chemistry

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