Affinity selection mass spectrometry (ASMS) is a general, high-throughput method to select and identify small molecule ligands from complex compound mixtures. Merck has advanced a specific ASMS approach termed ALIS (Automated Ligand Identification System), a two-dimensional LC/MS system in line with high-resolution mass spectrometry, to routinely assess one million compound / target encounters per day. This high throughput capability, while traditionally employed for small molecule hit identification, has recently been adapted to deconvolute molecular targets of phenotypically active compounds of unknown mechanism, in an approach termed Protein Array ALIS (PA-ALIS), and to quantitatively rank order the binding affinity of medicinal chemistry analogs in complex mixtures (Protein Titration or PT-ALIS). The PT-ALIS method, when combined with nanoscale parallel or mixture synthesis permits identification of analogs most likely to exhibit potent functional activity starting from very small quantities of material and without need for compound purification prior to biological assay. An introduction to ALIS and the novel application to medicinal chemistry and target identification will be presented.

ALIS affinity selection in pharmaceutical discovery

254th National Meeting (2017)

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