Filtering hits to leads

An extensive range of in-house filters was applied to remove toxic, reactive and undesirable functionality. This set of filters has been built up based on years of experience with HTS screening and medicinal chemistry optimisation of hits to leads. A special focus was made... 

Reactive, unstable compounds, as well as covalent binders, can be removed from screening collections by substructure searches [21, 22]. At Roche, a global team of experienced medicinal chemists has defined more than 100 functionalities which are reviewed at regular intervals. This list has been augmented by unwanted features (e.g., polyacids, alkyl aldehydes, polyhalogenated phenols, etc.) which are chemically unattractive starting points for a hit-to-lead optimization, because they often result in non-optimizable SAR patterns. These chemotypes have been coded into Markush-type substructures for automated detection and removal of unwanted compounds. However, we need to stress that these filters are fully customizable, and removed chemotypes can be restored if required. 

Scientists at AstraZeneca shared their experiences with their historical compound collections, which prompted them into defining a number of selection criteria in order to filter out compounds of little value for the hit-to-lead process [27]. Subsequently, this led to a compound collection enhancement program. 

Zebrafish Brachydanio/Danio rerio) embryos can be produced in large numbers and carry sufficient nutrients within the egg sack to allow development within micro plate volumes [52, 53]. Mutation frequency has been estimated indirectly using transgenic fish [54[ and UDS, comet, MNT and alkaline filter elution methods have been used effectively [55]. At present, there has been insufficient study of the model to understand predictivity of mammalian genotoxicity, and none of the methods has been demonstrated at throughputs sufficient for hit and lead screening. 

To demonstrate text to lead prototype, a PubMed query was constructed with keywords malaria in conjunction with drugs filtered by title category in the MegaMiner portal. The limit on abstracts to be returned as hits was set to 15. This... 

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