High Throughput Analysis of Combinatorial Libraries Encoded with Electrophoric Molecular Tags

Very valuable resources for the discovery of biologically active agents are encoded combinatorial libraries of small molecules. A binary encoding protocol employing electrophoric molecular tags (ECLiPSe technology) has been developed at Pharmacopeia. A series of quality control (QC) protocols to ensure the highest degree of library has also been put into practice. This protocol, sets of synthons are serially combined through split-and-pool or direct divide synthesis in tandem with the incorporation of binary sets of electrophoric tags on solid support. Quality control steps occur throughout the entire library construction pipeline. To ensure a successful library synthesis and production elution Extensive synthon profiling, rigorous analysis of QC compounds, final confirmation of library chemistry (library QA), and production-in-process-QC analysis are essential. Empirical information regarding overall fidelity and an indication of the performance of individual synthons is provided by both in-line and final library QA. The quality of large, encoded combinatorial libraries can be assessed by library QA, a powerful analytical protocol. Based on the combined application of tag decoding and single bead liquid chromatography/mass spectrometry (LC/MS), QA analysis would be virtually impossible to carry out without an encoding strategy due to redundant masses produced during split synthesis. The statistical theory and its application to library assessment are analogous to the accepted statistical sampling practices used in the industry to ascertain the quality of mass-produced material. The simplicity of tag reading and rapid acquisition of structure activity relationship (SAR) information is arguably the most significant advantage of encoding technology vs. other deconvolution techniques. Library QA serves to substantiate and enhance the value of nascent SAR obtainment from library screening.