Screening hit

The process of tracking screening hits and determining which chemical series is likely to produce a fruitful lead involves the verification of activity within a series of related... 

Fig. 10 Screening hit and higher affinity benzimidazoles for HCV RNA internal ribosome entry site (IRES) IIA subdomain...

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Not only does the limited diversity of the compound database curtail the choice of lead, the process for assessing screening hits to see if they define a tractable lead is also limited by resources, particularly in those specialist assays that would predict the ability of the chosen lead class to successfully yield an approval in a particular therapeutic field. The process is therefore driven mainly by consideration of activity against the target. Therefore chemotypes with adequate but less than maximal potency for the target but freedom from damaging side activity remain undetected in this process. 

Two recent communications described the hit-to-lead optimization which ensued from the original screening hit 10 [82,83]. From this research, four new... 

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

Validation and Preliminary Optimization of Primary NMR Screening Hits... 

The SHAPES Linking Library was designed to facilitate the use of combinatorial chemistry to follow up screening hits [11]. This library consists primarily of commercially available compounds containing two drug-like scaffolds connected by a linkage that is synthetically accessible. To construct this library, a database of commercially available compounds was filtered to select for drug-likeness and the presence of the desired molecular... 

The use of combinatorial chemistry to produce libraries of compounds is pivotal in drug discovery. Screen hits need to be analyzed to identify the structure of the individual active component. Large numbers of samples containing only small quantities of complex mixtures require... 

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