Screening hits, promiscuous

Hit compounds that exhibited at least 4 of the 9 available pharmacophores and had the lowest promiscuity were selected. Using these simple criteria, 186 compounds were chosen for screening, yielding 16 compounds that were specific for the A3 adenosine receptor, 3 more that were specific for the Aj receptor and a further 6 that were specific for the A2A receptor. Subsequently, 6 more examples were found that bound specifically to the A2B adenosine receptor, one of which was highly specific with a value below 100 nm. The results for the Aj, A2A 3 adenosine receptors are shown graphically in Figure 9. 

Researchers from BMS have detailed the results of their efforts to enhance their HTS process [34]. Their papers discuss the subjectivity of the typical chemical structure triage process as it relates to HTS analysis, a topic worth some investigation by anyone involved in this type of selection process. With the aim of reducing subjectivity in this area, the authors systematically review their filters for physicochemical properties (this topic discussed in more detail below) and unwanted chemical moieties. Much of the work is aimed at understanding and detecting promiscuous compounds - those that initially appear to be hits in many screens (this topic discussed in more detail below). Importantly, the authors have made some of the related tools available for public use. 

For frequent hitter analysis, we defined a frequent hitter score that depends on the number of screens in which a compound participated and on the number of screens where this compound was a hit We aimed at identilying a simple, empirical score that allows us to rank compounds with respect to their promiscuity, also in cases where compounds where tested in a different number of assays. A biological assay system is modeled as a biased coin that yields hit or non-hit with certain probabilities and the various assays to which a compound is subjected as a sequence of independent coin flips. Thus, we use a binomial distribution function to estimate the relative probabiUty of identifying a compound as a hit n times in k independent assays by chance. The probabiUties for the events hit and non-hit were estimated empirically from a set of assays. 

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