Chemical Libraries: Screening for Biologically Active Small Molecules
Ansgar Schuffenhauer · Wiley Encyclopedia of Chemical Biology · 2008
Abstract The screening of chemical libraries is one of the major sources for new leads in drug discovery. The large size of chemistry space compared with the library sizes that are feasible to screen requires careful selection of the compounds for the screening library to maximize screening success. Besides issues around technology compatibility and chemical tractability of the compounds, the main objective is to increase the probability of obtaining hits for the screened targets. Diversity selection approaches have often shown only limited success. In the absence of any knowledge, it is proposed to screen smaller “lead‐like” ligands with preference. When knowledge about the target is available, it can be used for target‐focused compound selection or for library design. In the screening process, physical high‐throughput screening (HTS) can be combined with virtual screening either to avoid the high‐throughput primary screen of the whole library or to limit false negatives by combining primary HTS and virtual screening results. Screening an initial subset then using the results obtained to predict likely hits for subsequent screening rounds in sequential screening can lessen the number of compounds to be screened, but it causes a greater logistics effort and has the risk of missing compounds that are not well represented structurally by the initial set. Data analysis and visualization of the screening results are a necessary final step of a screening campaign to ensure that the prioritization of compounds followed up is based on all available relevant information.