ANYL 345 |
| The combination of separations with mass spectrometry offers a powerful solution to many of the challenges faced in biomolecular screening and is often adaptable to most small molecules and permits use of native substrate at biologically relevant concentrations without the danger or expense of radioactive substrates. In these MS based assays, ultra fast, high-resolution separations prevent interference of the substrate with the substrate product even in the presence of drug candidate compounds. Traditional assays generally cannot readily adapt to the challenges / interferences encountered from the drug candidate compounds. The frequent result is missed hits and a large number of false positives (often >10 fold the number of leads). In contrast, separations/MS based assays can readily incorporate MS/MS or HRMS into the assay to anticipate the challenges/interferences encountered from the drug candidate compounds and virtually eliminate false positives by achieving sufficient molecular specificity. In addition, separations/MS often have enough excess precision (5% RSD) and dynamic range (3 orders of magnitude) to easily distinguish hits from noise (even in difficult activation assays) and yield high Z' factors (Z' > 0.7). In this presentation, results from GC/MS and LC/MS based screens are presented. While MS based measurements are not likely to ever become as fast as optical measurements, the observation of this work is that the total screening project time required is very similar. Rapid assay development compensates for the extra measurement time required. Furthermore, hits from separations/MS based screening tend to be validated in secondary assays, presumably due to the lack of false positives. Hits, free of false positives, save resources as their associated projects progress into/through the lead optimization phase. Better resource utilization coupled with the ability to perform otherwise infeasible screens make separations/MS a tool of choice for HTS. |
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Analytical Technology for Drug Discovery
8:30 AM-11:50 AM, Tuesday, August 21, 2007 BCEC -- 105, Oral
Division of Analytical Chemistry |