New combichem QC standards guard the supply of compounds and ensure HTS

T he dictionary definition of noise is any signal that does not convey useful information and interferes with the desired signal. For example, electrical noise limits the sensitivity of radio receiving systems and, when present at high enough levels, may cause false outputs from digital circuits. The signal-to-noise (S/N) ratio is therefore an important factor when evaluating electronic equipment. In the same way, the S/N ratio of biological screenings is extremely important for the success of drug lead discovery, and it is predominantly determined by the quality of compounds that are screened. Impurities are the main contributors to screening noise. Besides archive compounds, most chemical supplies currently used for screening come from high-throughput organic synthesis (HTOS) or combinatorial synthesis (1). HTOS and combinatorial synthesis are highly effective in producing numerous compounds. However, the quality of compounds made by these methods in the past decade is only average or, in some cases, below average by organic chemistry standards. Three key parameters characterizing the quality of a synthetic product are its identity, purity, and yield (quantity). In traditional organic synthesis, identity is obtained primarily by NMR spectroscopy, purity by elemental analysis, and quantity by the weight of the purified compound. The application of these compounds in biological screenings is therefore unambiguous. However, compound characterization has undergone a dramatic shift in the move from traditional methods to HTOS and combinatorial synthesis. Because of the limited throughput of traditional analytical methods, a very large number of library compounds, each present in a low quantity, cannot be thoroughly characterized. NMR cannot be used for analyzing every member in large combinatorial libraries because of the slow spectral interpretation process, even though high-throughput spectral acquisition has been achieved (2). Elemental analysis is not feasible because of its low throughput and the inadequate sample quantity from combinatorial synthesis. Weighing is cumbersome for compounds synthesized in individual vials and is not feasible for synthesis performed on a multiwell plate. Because of these deficiencies, most combinatorial compounds used in high-throughput screening (HTS) lack some information on identity, purity, and quantity. Using compounds of questionable quality in HTS always generates ambiguous results. Better control and improvement of the purity and yield of desired compounds are of utmost importance in combinatorial chemistry. Because of the various ways to measure the purity, chemistry laboratories have set quite different quality control (QC) criteria before screening.