A guide to drug discovery

Combinatorial compound libraries for drug discovery: an ongoing challenge

Key Points

  • Combinatorial chemistry has been widely adopted by the pharmaceutical industry in the past decade. However, owing to perceived “failures” with this technology, the pharmaceutical industry has been sourcing an increasing proportion of compounds for screening by highly automated traditional solution-phase chemistry followed by HPLC/MS purification.

  • This movement away from solid-phase, numerically large, combinatorial library synthesis results from the current industry view that can be summarized by the following statements:

  • The quantitation of solid-phase chemistry, especially at the single bead level, is very difficult and not generally applicable.

  • Solid-phase chemistry is limiting with respect to the diversity of chemistries that can be carried out, and most of the successful solid-phase chemistries are very dependent on amide bond formation. The non-amide-bond chemistries that have been successfully enabled on solid-phase are few and so well explored that intellectual property issues now compromise their use by others.

  • Encoding strategies associated with library synthesis are unreliable with respect to linking compound identity with assay outcome. Mix-and-split synthesis strategies are precluded for lack of an acceptable encoding methodology, and require single-bead assay methods that are compromised by the quality of solid-phase synthesis.

  • Solid-phase chemistry should be restricted to the synthesis of discrete compounds (parallel synthesis) and include purification of each compound, with a target yield of 10 mg final purified compound.

  • In this article, each of the above issues is addressed in terms of technological developments that might offer a potential solution.


Almost 20 years of combinatorial chemistry have emphasized the power of numbers, a key issue for drug discovery in the current genomic era, in which it has been estimated that there might be more than 10,000 potential targets for which it would be desirable to have small-molecule modulators. Combinatorial chemistry is best described as the industrialization of chemistry; the chemistry has not changed, just the way in which it is now carried out, which is principally by exploiting instrumentation and robotics coupled to the extensive use of computers to efficiently control the process and analyse the vast amounts of resulting data. Many researchers have contributed to the general concepts as well as to the technologies in present use. However, some interesting challenges still remain to be solved, and these are discussed here in the context of the application of combinatorial chemistry to drug discovery.

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Figure 1: Analytical constructs for combinatorial chemistry.
Figure 2: Product analysis using an analytical construct.
Figure 3: Assay operation using an analytical construct.
Figure 4: Optimization of reaction protocols using an analytical-construct approach.
Figure 5: An example of a complete process using the analytical-construct approach.
Figure 6: Encoding strategies.
Figure 7: Assembly of the code block.
Figure 8: Procedure for solution-phase assays with encoded bead-based libraries.
Figure 9: Decoding data using a statistical approach.


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The authors would like to thank the members of the Diversity Sciences Department at GlaxoSmithKline for the fine work carried out on this technology over the period 1993–2001.

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Correspondence to H. Mario Geysen.

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In solid-phase synthesis, the compounds being made are attached (usually by a linker group) to insoluble, functionalized, polymeric material (usually beads), allowing them to be readily separated (by filtration, centrifugation, and so on) from excess reagents, soluble reaction by-products or solvents.


Strategy to identify members of a combinatorial bead-based library. A surrogate analyte is associated with each member of the combinatorial library. This is often achieved by the use of tags attached to the beads on which the library members are assembled, which allows the reaction history of each bead to be determined.


The solid support (for example, beads) is divided into portions, each of which is subjected to reaction with a single monomer. Combining these portions results in a single batch of solid support bearing a mixture of components. Repetition of the divide, couple, recombine processes results in a library in which each discrete particle of solid support carries a single library member.


The knowledge that an even number of code peaks (usually four or six) indicates whether or not a reaction product has overwritten one of the peaks. Should this occur, it is still possible to read the code by inference, providing only one overwriting event has occurred.

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Mario Geysen, H., Schoenen, F., Wagner, D. et al. Combinatorial compound libraries for drug discovery: an ongoing challenge. Nat Rev Drug Discov 2, 222–230 (2003). https://doi.org/10.1038/nrd1035

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