Hit rates, screening

Validation of Antitarget Pharmacophore Models 6.3.3.1 Virtual Screening Hit Rates and Yields... 

SeeDs screening hit rates for 12 protein targets. With kind permission from Springer Science+Business Media Journal of Computer-Aided Molecular Design, 23,2009,603, l-Jen Chen and Roderick E. Hubbard, Table 4... 

The validated HTS assay was then employed to screen a 100,000-compound library against SARS CoV. The hit rate for the library in a single-dose format was determined to be approximately 0.8%. Screening of the three libraries resulted in the identification of several novel compounds that effectively inhibited the CPE of SARS CoV in vitro. Three hit compounds, shown below, were identified as promising lead candidates for further evaluation. 

Table 6.3 Hit rate and yield from virtual screen of MDDR test set database using both a- A pharmacophores as selection filter [16].

Table 6.4 Hit rate, yield and enrichment factors for the top 5% scorers from virtual screen of M DDR test set database using both...

Competition between components of a mixture becomes more likely as the hit rate and pool size increase. For a 10% hit rate, competing hits will be found in 26% of mixtures of ten compounds, but only 2.7% in mixtures of three [11]. Unless mixtures are deconvo-luted, competition can lead to false negatives when the competing compounds have different affinities. For screens using protein detection, competition can also produce false positives due to the additive effect of multiple weak binders. Competition can be controlled by limiting the size of mixtures and pooling dissimilar compounds to reduce the likelihood of two compounds binding at the same site. 

One-third of these appeared in the actives for the assay, which was defined using a 30% inhibition threshold. The overall hit rate for the assay was 2.0% in other words, 20% of the actives were false positives due to extreme optical interference with the assay readout. This number rises depending on the level of initial fluorescence used as a cutoff in the selection scheme used by the project team at the time, almost half of the actives were rejected as false positives on the basis of the initial fluorescence readings. The corporate screening collection has been reformatted since then, and many of these problem compounds have been removed. 

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