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Combinatorial chemistry: starting the second decade

The Pharmacogenomics Journal volume 1, pages 229–232 (2001)Cite this article

About 20 years ago, the industry-wide cost of a new drug was around $100 million (USD). Toward the end of the 1980s, that cost had risen to $250 million. Biological testing had entered the high-throughput screening era, creating the ability to test more compounds than previously achievable. This added to the demand for more compounds with new properties. In the early days of modern drug discovery, 5000 to 10 000 compounds would be evaluated for each drug development lead found. A decade after the introduction of high-throughput screening technologies, this efficiency in generating drug development leads had declined to 120 000 compounds tested per lead.1 In the last few years, this efficiency generally has declined further still. Among the reasons for the declining performance are the molecular targets being pursued (eg, more protein–protein interactions) and the high attrition rates when testing for efficacy and safety needed in drug leads. Into this climate of demand for large numbers of novel compounds, combinatorial chemistry was born. Combinatorial chemistry was a technological revolution because it provided a means to generate new compounds—ranging from a few to many thousands of different molecules—in a short period of time. It is also a method generally accessible to laboratories big and small, thus making the discovery of small molecule drugs no longer the exclusive province of major drug companies.

In some ways, however, combinatorial chemistry has been disappointing for pharmaceutical scientists. A decade after its introduction, the industry-wide cost of developing a new drug has ballooned to the $500–600 million range, and we still see only a few exciting drug development leads entering our pipelines. Indeed, generic combinatorial chemistry collections have performed worse than traditional drug company compound collections in generating leads. In this Perspective, I will briefly introduce the basic concepts of combinatorial chemistry, describe its strengths and weaknesses with an eye to efficiencies, and highlight some ongoing changes to enhance performance. The scope will be restricted to small compounds made by synthetic chemistry, and not biologically generated libraries such as phage display.

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  1. Departments of Chemistry & Discovery Biology, Selectide, the Combinatorial Chemistry Center of Expertise for Aventis Pharmaceuticals, Tucson, AZ, USA

    D S Thorpe

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Correspondence to D S Thorpe.

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Thorpe, D. Combinatorial chemistry: starting the second decade. Pharmacogenomics J 1, 229–232 (2001). https://doi.org/10.1038/sj.tpj.6500045

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