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J Cheminform. 2015 Nov 17;7:55. doi: 10.1186/s13321-015-0103-5. eCollection 2015.

Target enhanced 2D similarity search by using explicit biological activity annotations and profiles.

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National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, 8600 Rockville Pike, Bethesda, MD 20894 USA.



The enriched biological activity information of compounds in large and freely-accessible chemical databases like the PubChem Bioassay Database has become a powerful research resource for the scientific research community. Currently, 2D fingerprint based conventional similarity search (CSS) is the most common widely used approach for database screening, but it does not typically incorporate the relative importance of fingerprint bits to biological activity.


In this study, a large-scale similarity search investigation has been carried out on 208 well-defined compound activity classes extracted from PubChem Bioassay Database. An analysis was performed to compare the search performance of three types of 2D similarity search approaches: 2D fingerprint based conventional similarity search approach (CSS), iterative similarity search approach with multiple active compounds as references (ISS), and fingerprint based iterative similarity search with classification (ISC), which can be regarded as the combination of iterative similarity search with active references and a reversed iterative similarity search with inactive references. Compared to the search results returned by CSS, ISS improves recall but not precision. Although ISC causes the false rejection of active hits, it improves the precision with statistical significance, and outperforms both ISS and CSS. In a second part of this study, we introduce the profile concept into the three types of searches. We find that the profile based non-iterative search can significantly improve the search performance by increasing the recall rate. We also find that profile based ISS (PBISS) and profile based ISC (PBISC) significantly decreases ISS search time without sacrificing search performance.


On the basis of our large-scale investigation directed against a wide spectrum of pharmaceutical targets, we conclude that ISC and ISS searches perform better than 2D fingerprint similarity searching and that profile based versions of these algorithms do nearly as well in less time. We also suggest that the profile version of the iterative similarity searches are both better performing and potentially quicker than the standard algorithm.


2D similarity search; Iterative similarity search; Iterative similarity search with classification; Nearest neighbor; Profile

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