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Combinatorial chemistry has opened a new realm of chemical entities in the search for novel therapeutics. Combinatorial chemistry is currently adding hundreds of thousands of compounds to similar numbers available from years of synthesis by medicinal chemistry. It is not unreasonable to expect that over the next several years, nearly a million compounds will be available for screening against each therapeutic target. The number of potential targets will also be increasing with the advances in genomics. With the increasing number of compounds to be screened against an increasing number of targets, it is becoming increasingly difficult and costly to obtain the required amounts of key biological material needed to screen these compounds. One obvious solution is to miniaturize the assays so that the biological reagent supply doesn't need to increase. To this end, we have developed an ultra-high throughput screening system comprised of a new plate design (9600-well), detection system, and liquid handling system. This new format is capable of performing assays in as little as 0.2 Al.The results obtained from this system compare favorably to those obtained in the standard 96-well format.

Combinatorial chemistry has opened a new realm of chemical entities in the search for novel therapeutics. Combinatorial chemistry is currently adding hundreds of thousands of compounds to similar numbers available from years of synthesis by medicinal chemistry. It is not unreasonable to expect that over the next several years, nearly a million compounds will be available for screening against each therapeutic target. The number of potential targets will also be increasing with the advances in genomics. With the increasing number of compounds to be screened against an increasing number of targets, it is becoming increasingly difficult and costly to obtain the required amounts of key biological material needed to screen these compounds. One obvious solution is to miniaturize the assays so that the biological reagent supply doesn’t need to increase. To this end, we have developed an ultra-high throughput screening system comprised of a new plate design (9600-well), detection system, and liquid handling system. This new format is capable of performing assays in as little as 0.2 μl. The results obtained from this system compare favorably to those obtained in the standard 96-well format.

Low resolution methods can provide exact mass data comparable to that obtained with high resolution instrumentation and offer potential advantages in throughput and robustness. However, low resolution exact mass techniques have realized limited use largely because of the possibility of errors caused by unresolved interferences. Here the utility of statistical peak shape analysis for determining unresolved interferences at low resolution is considered. Equations describing the effect of unresolved interferences on statistical peak shape parameters are developed and used to investigate the extent to which evaluations of peak shape can be used to reduce the likelihood of mass measurement errors. Peak shape analysis is shown to be a highly effective and sensitive method of determining unresolved interferences. Mass measurement errors resulting from undetermined interferences are found to increase with increasing relative abundance of the interfering peak, to increase with decreasing resolution, and to increase with decreasing precision in the intensity measurement. At low resolution, undetermined interferences as small as a few percent relative abundance can produce mass measurement errors in excess of 5 ppm. Peak shape analyses alone do not appear adequate to eliminate the risk of significant mass measurement errors resulting from unresolved interferences at low resolution.

A mass spectrometric strategy for the direct determination of the structures of compounds on active beads selected from combinatorial mixtures by ultrahigh throughput screening is presented. Complementary mass spectrometric data (exact mass and MS/MS spectra) were obtained in a single acquisition using automatic function switching. Analyses of these data produced unequivocal identifications of the structure in 70% of the cases. The automatic computer analyses generated definitve solutions in 80% of the analyses. The remainder of the beads contained mixtures of components or components not in the enumerated library (either by‐products or degradants of expected components). In these cases the identity of the compounds were conclusively deduced from manual interpretation of the mass spectral data. The putative identities of all active compounds were confirmed by resynthesis and comparison of the mass spectrometric data for the putative and authentic structures. © 1998 John Wiley & Sons, Ltd.

A mass spectrometric strategy for the direct determination of the structures of compounds on active beads selected from combinatorial mixtures by ultrahigh throughput screening is presented. Complementary mass spectrometric data (exact mass and MS/MS spectra) were obtained in a single acquisition using automatic function switching. Analyses of these data produced unequivocal identifications of the structure in 70% of the cases. The automatic computer analyses generated definitve solutions in 80% of the analyses. The remainder of the beads contained mixtures of components or components not in the enumerated library (either by-products or degradants of expected components). In these cases the identity of the compounds were conclusively deduced from manual interpretation of the mass spectral data. The putative identities of all active compounds were confirmed by resynthesis and comparison of the mass spectrometric data for the putative and authentic structures. © 1998 John Wiley & Sons, Ltd.