Screening collection

In the current era neutral compounds are important simply because there are so many of them especially in screening collections made in automated chemistry for HTS. Other things being equal, a compound with an ionizable moiety is preferred to a neutral compound. By definition a neutral compound will not give an acid or basic pJCj value. Some essentially neutral compounds can form aqueous unstable salts. This most commonly occurs when an extremely poorly basic compound is dissolved in organic solvent and the salt is precipitatated, e.g. by bubbling in HCl gas. 

Having said all this, a recent report from a major pharmaceutical company with one of the largest reported screening collections revealed that just over 50% of their current lead optimization efforts invoke a "fast follower" approach [114]. Why is this One might speculate that as most companies work on the same targets these days chemists find it easier to "patent bust" than wait for the results of an HTS campaign which may take months to develop. Possibly, when more novel targets are identified, HTS of enhanced collections will deliver upon the promise that they hold. 

Wu et al. [388] carried out measurements of the enrichment of Atrazine on the micro surface water of an estuary. These authors used a micro surface water sampling technique with a 16 mesh stainless steel screen collecting bulk sampled from the top 100-150 pm of the surface. Atrazine concentration in the actual micro surface was estimated to vary in the range 150-8850 pg/1. 

Focussed Dl V E R S I T Y needed A good screening collection incorporates all these facets. 

Fig. 3.2 Occupancy of 222705-element GaP space for a typical screening collection.

When building HTS screening collections, it has long been the practice not only to proactively select molecules for inclusion but also to deselect compounds that have undesirable properties. Typical deselection criteria are in silico derived chemical reactivity descriptors designed to remove compounds that might give an inappropriate mode of action or result in toxic events [6]. Other properties derived from the molecular... 

Many corporate screening collections may inadvertently contain two or more samples of the same compound, for example, from different synthetic batches. Examining the results from a large number of such replicate samples can provide a useful way to assess the upper limit of variability in the primary assay. This represents an upper limit because other factors such as compound degradation can account for an unknown amount of the observed variability. Such replicate samples can also be filtered out if desired. 

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. 

The 5 k actives with percent inhibition of 25 to 40% and that feU into clusters of less than five compounds were treated separately using BCUT diversity analysis, as described in Section 6.2.5. A cell-based selection biased by primary activity from six bins per each of six axes yielded 1258 compounds. The combined selection from filtering, clustering, and diversity totaled 6986 compounds representing 3337 ring scaffolds and was submitted for confirmation assays. Note that the full set of 16 k filtered actives contained 9254 ring hashcodes, so the selected set covers 36.1% of the represented scaffolds. Because of the presence of duplicate samples in the corporate screening collection, 7275 samples were pulled and assayed. 

Primary metabolites, co-factors, and marketed drugs form additional sets of biologically relevant and validated compounds that constitute an essential component of a comprehensive screening collection. 

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