Wednesday, 7 October 2015

Redesigning a chemical library to bolster high-quality hit series identification

Well-designed chemical libraries are a critical tool in the race for drug-discovery in an intensely competitive pharmaceutical marketplace. Success in early stages of the drug-discovery process depends on access to quality sample libraries that balance the requirements for chemical diversity and redundancy. Coupled with accurate, rapid and cost-effective HTS technologies and instrumentation, the AMRI Synthetic Compound Collection (ASCC) will improve the chances of identifying high quality hit series through HTS.
As the costs of drug development rise, pharmaceutical companies continue to require high-quality data and cost-effective methods starting with the earliest stages of drug discovery. High-throughput screening (HTS) remains a powerful tool in early-stage research, which allows project teams to identify hits against a target of interest1 . Yet screening of compound libraries remains an expensive process. In order to provide customers with the best chance to identify valid hits and produce successful hit-to-lead investigations, attractive compound libraries need to incorporate collections of diverse compounds that contain clusters of structurally similar analogs. This design approach needs to be achieved while carefully selecting compounds within various physical and chemical property constraints. Well-designed chemical libraries will have greater potential to meaningfully correlate chemical structure of a hit with interactions at its intended target2 . A high quality library in turn increases confidence in the quality of compounds identified as hits.
Much effort in the past decade has been directed to making the HTS process more efficient3 . These efforts include developments focused on improvement to instrumentation as well as screening processes. Screening techniques have also evolved in order to screen libraries of various sizes from a few hundred fragments to large corporate libraries with millions of samples. Parallel to these efforts, chemoinformatics tools have become powerful aids in designing better libraries and evaluating screening results in the context of chemical property as well as structural content of the samples represented in a library4 . Presented here is the selection of an HTS library of intermediate size. To build this quality library, compounds were selected by filtering out those with structural features related to poor assay outcome such as aggregation, reactivity or lack of target specificity and filtering compounds based on desirable ranges of properties such as logP5 . Additionally, compounds were selected with an eye towards chemical diversity and inclusion of small sets of analogs. The resulting library is also analyzed to show good coverage of shape and biological space. All these features have been implicated in positive outcomes of HTS campaigns: The generation of good chemical starting points for hit-to-lead programs
http://vertassets.blob.core.windows.net/download/c3d28fcf/c3d28fcf-8f65-45c3-aaed-0c3090c5f047/welldesignedchemical_whitepaper.pdf

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