Many drug discovery lead optimization projects get their starts from a high-throughput screening (HTS) campaign, and so by improving the quality of the HTS deck we can improve the quality of drug candidates, or the likelihood of finding a compound that can be progressed to a drug candidate. Janssen Pharmaceutical Research and Development has built a collection of library molecules by implementing several strategies for external compound acquisitions as well as internal synthesis.<br/>In this project, we analyzed the performances of each of those compound collections against a set of selected targets (GPCRs, Ion channels, Kinases, PPIs, cytokines etc.). We have classified the library into two broad categories: Internal (internally synthesized compounds) and external (Off-the-shelf purchased compounds) collections. The comparison of performance between these two categories was done by considering the primary, confirmation and dose response hit rates. Our analysis revealed that internal compounds have higher average hit rates than external ones, but that the compounds with the highest average hit rates over a set of targets are those (either internal or external) that are known to be active at one or more other, distinct targets. This observation led us to accumulate a set of several thousand promising compounds which tend to be active in multiple targets. To check for promiscuity, we performed an extensive screening campaign with all these active compounds (specially which appear to active in multiple targets) to identify possible aggregation in addition to filtering out non-drug<b>-</b>like compounds from our screening deck. From this analysis, we aim to learn the pattern of unique descriptor landscape and the diversity in scaffolds of the compounds with the highest hit rates, and to use them to improve our future external acquisition strategies to enrich our screening library collections, as well as to reform our plating strategy to accelerate future HTS campaigns.<br/>

Library enhancement through performance analysis of different components of high-throughput screening library against a variety of targets

256th National Meeting (2018)

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