Determining synthetic failures in combinatorial libraries by hybrid gas-phase separation methods

A combinatorial tripeptide library having the general form D-Glu-Xxx-Xxx-CO NH2 has been synthesized using a standard mix and split synthetic protocol that is expected to produce 676 components. All components of the mixture w ere analyzed using a new high-resolution ion mobility/time-of-flight mass s pectrometer coupled with an electrospray ionization source. In this approac h ions are separated by differences in their gas-phase mobilities prior to being introduced into the mass spectrometer for mass-to-charge analysis. Th e peptide library includes a wide range of different sequence, structural, and stereo isomers; trends in the number of expected and resolved isomers t hat are observed at each m/z ratio allow specific synthetic steps that have failed to be identified, even in the presence of other isomers. Informatio n about the relative abundances of different isomers should dramatically im prove the reliability of binding affinity studies from direct analysis of m ixtures. (J Am Soc Mass Spectrom 2000, 11, 352-355) (C) 2000 American Socie ty for Mass Spectrometry.