Quantitative high-throughput screening advance
For those readers actively engaged with or otherwise interested in drug screening, this open-access article by Inglese et al from the NIH Chemical Genomics Center is welcome news and good reading. The qHTS approach by Inglese at al, in which a 5-fold dilutional titration of each sample compound is represented across seven experimental plates (each compound at the same relative plate position to avoid positional errors), resulting in a 7x library replication, addresses many of the problems that limit the utility of HTS, particularly HTS of combichem libraries, with their typically limited structural diversity. They show, convincingly, that this multi-concentration approach yields fewer false positives and, very importantly, fewer false negatives of active compounds, including active compounds with high potency and efficacy as compared with single or double concentration screening, at least in the context of a luminsecent enzyme-based assay with high signal to noise ratio. They are now testing their method with cell-based assays. I suspect that some drug companies and discovery-only houses have quietly been using a similar approach for some time, but I believe this is the first published description of the technique in practice. Expect companies who haven’t adopted the technique to begin testing it for themselves in the near future. It promises to result in more hits, with fewer false positives, and earlier SAR, which means better drug candidates sooner. What’s not to like?
