BACKGROUND: Selection experiments involving chemical libraries are routinely used in the pharmaceutical industry for finding and optimizing lead compounds. In principle, almost any process involving a binding event or a reaction could be probed systematically with chemical libraries prepared by combinatorial synthesis. Traditionally, however, the vast majority of library members cannot be monitored during the selection, making a systematic correlation of structure and activity difficult. To interpret selection experiments on the level of all library components, monitoring technologies are required that give a unique and quantitative spectroscopic signal for every compound in a mixture. RESULTS: Quantitative matrix-assisted laser desorption mass spectrometry of libraries of porphyrins and peptide-DNA hybrids consisting of 2-35 compounds is described. Porphyrin libraries were subjected to in vitro selections for liposome incorporation and binding to a protein pocket. It was shown that mesohydroxyphenyl substituted porphyrins, known high activity photosensitizers of tumors, are preferentially incorporated in liposome membranes. A mixture of peptide-DNA hybrids was assayed for the nuclease stability of its components. CONCLUSIONS: Small libraries of non-isobaric compounds can be exhaustively or near-exhaustively monitored by mass spectrometry. Monitored selection experiments can yield detailed structure-activity maps in a single experiment, speeding up drug discovery and the probing of biochemically relevant recognition events. It is proposed that monitored assays for target binding, membrane partitioning, and biostability could be run in parallel, to select drug candidates combining several favorable properties in 'multidimensional' selection experiments.
BACKGROUND: Selection experiments involving chemical libraries are routinely used in the pharmaceutical industry for finding and optimizing lead compounds. In principle, almost any process involving a binding event or a reaction could be probed systematically with chemical libraries prepared by combinatorial synthesis. Traditionally, however, the vast majority of library members cannot be monitored during the selection, making a systematic correlation of structure and activity difficult. To interpret selection experiments on the level of all library components, monitoring technologies are required that give a unique and quantitative spectroscopic signal for every compound in a mixture. RESULTS: Quantitative matrix-assisted laser desorption mass spectrometry of libraries of porphyrins and peptide-DNA hybrids consisting of 2-35 compounds is described. Porphyrin libraries were subjected to in vitro selections for liposome incorporation and binding to a protein pocket. It was shown that mesohydroxyphenyl substituted porphyrins, known high activity photosensitizers of tumors, are preferentially incorporated in liposome membranes. A mixture of peptide-DNA hybrids was assayed for the nuclease stability of its components. CONCLUSIONS: Small libraries of non-isobaric compounds can be exhaustively or near-exhaustively monitored by mass spectrometry. Monitored selection experiments can yield detailed structure-activity maps in a single experiment, speeding up drug discovery and the probing of biochemically relevant recognition events. It is proposed that monitored assays for target binding, membrane partitioning, and biostability could be run in parallel, to select drug candidates combining several favorable properties in 'multidimensional' selection experiments.
Authors: Christopher Farley; N V S Dinesh K Bhupathiraju; Bianca K John; Charles Michael Drain Journal: J Phys Chem A Date: 2016-09-14 Impact factor: 2.781