Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening (original) (raw)
Figure 1
Workflow for phenotypic screening of S. mansoni.
The workflow was prosecuted with the Microsource Discovery Inc.'s “Spectrum” and “Killer” collections that together comprise 2,160 (1,992 unique) compounds, including 821 drugs approved for use with humans (http://www.msdiscovery.com/). The goal was to interface this parasite with the 96-well plate-formatted small molecule libraries available at the UCSF Small Molecule Discovery Center (SMDC; http://smdc.ucsf.edu/) and common elsewhere, thereby accelerating throughput and facilitating screen automation. Schistosomula are placed at the apex of a three-component workflow that subsequently incorporates screens against adult parasites in vitro and finally an animal model of infection to measure in vivo efficacy. Times at which phenotypes were recorded in vitro are indicated in hours and days Two GO/NO GO workflow filters allow for prioritization of the ‘hit’ compounds in vitro. The numbers of ‘hits’ generated at various points in the workflow are indicated in bold typeface. Data arising from each of the three screening components are posted online as a flat file at The Sandler Center's ‘Low Hanging Fruit” website (http://pathology.ucsf.edu/mckerrow//fruit.html), and in a cross-searchable format, at the database maintained by Collaborative Drug Discovery (CDD Inc.; (http://www.collaborativedrug.com/). For smaller numbers of compounds, the workflow need not be hierarchically prosecuted, rather every compound can be screened against both schistosomula and adults.