Analysis of in vitro bioactivity data extracted from drug discovery literature and patents: Ranking 1654 human protein targets by assayed compounds and molecular scaffolds

<p>Abstract</p> <p>Background</p> <p>Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of publications updating both the hypothetical and successful human drug target statistics. However, listings of research targets that define the area between these two extremes are sparse because of the challenges of collating published information at the necessary scale. We have addressed this by interrogating databases, populated by expert curation, of bioactivity data extracted from patents and journal papers over the last 30 years.</p> <p>Results</p> <p>From a subset of just over 27,000 documents we have extracted a set of compound-to-target relationships for biochemical <it>in vitro </it>binding-type assay data for 1,736 human proteins and 1,654 gene identifiers. These are linked to 1,671,951 compound records derived from 823,179 unique chemical structures. The distribution showed a compounds-per-target average of 964 with a maximum of 42,869 (Factor Xa). The list includes non-targets, failed targets and cross-screening targets. The top-278 most actively pursued targets cover 90% of the compounds. We further investigated target ranking by determining the number of molecular frameworks and scaffolds. These were compared to the compound counts as alternative measures of chemical diversity on a per-target basis.</p> <p>Conclusions</p> <p>The compounds-per-protein listing generated in this work (provided as a supplementary file) represents the major proportion of the human drug target landscape defined by published data. We supplemented the simple ranking by the number of compounds assayed with additional rankings by molecular topology. These showed significant differences and provide complementary assessments of chemical tractability.</p

Quantitative assessment of the expanding complementarity between public and commercial databases of bioactive compounds

<p>Abstract</p> <p>Background</p> <p>Since 2004 public cheminformatic databases and their collective functionality for exploring relationships between compounds, protein sequences, literature and assay data have advanced dramatically. In parallel, commercial sources that extract and curate such relationships from journals and patents have also been expanding. This work updates a previous comparative study of databases chosen because of their bioactive content, availability of downloads and facility to select informative subsets.</p> <p>Results</p> <p>Where they could be calculated, extracted compounds-per-journal article were in the range of 12 to 19 but compound-per-protein counts increased with document numbers. Chemical structure filtration to facilitate standardised comparisons typically reduced source counts by between 5% and 30%. The pair-wise overlaps between 23 databases and subsets were determined, as well as changes between 2006 and 2008. While all compound sets have increased, PubChem has doubled to 14.2 million. The 2008 comparison matrix shows not only overlap but also unique content across all sources. Many of the detailed differences could be attributed to individual strategies for data selection and extraction. While there was a big increase in patent-derived structures entering PubChem since 2006, GVKBIO contains over 0.8 million unique structures from this source. Venn diagrams showed extensive overlap between compounds extracted by independent expert curation from journals by GVKBIO, WOMBAT (both commercial) and BindingDB (public) but each included unique content. In contrast, the approved drug collections from GVKBIO, MDDR (commercial) and DrugBank (public) showed surprisingly low overlap. Aggregating all commercial sources established that while 1 million compounds overlapped with PubChem 1.2 million did not.</p> <p>Conclusion</p> <p>On the basis of chemical structure content <it>per se </it>public sources have covered an increasing proportion of commercial databases over the last two years. However, commercial products included in this study provide links between compounds and information from patents and journals at a larger scale than current public efforts. They also continue to capture a significant proportion of unique content. Our results thus demonstrate not only an encouraging overall expansion of data-supported bioactive chemical space but also that both commercial and public sources are complementary for its exploration.</p

Current Topics In Medicinal Chemistry, 2007, accepted for publication Complementarity between public and commercial databases: new opportunities in medicinal chemistry informatics

The last two years have seen a dramatic expansion in public cheminformatics, as exemplified by the approximate five-fold growth of PubChem from over 50 contributing data sources. Consequently, medicinal chemists who were hitherto limited to commercial databases now also have access to public sources that they can download and/or query directly over the Web. The range of public sources, particularly where they link out to structured bioinformatic and biological data, already offer utilities that have no commercial equivalent. This work reviews compound content comparisons between selected public and commercial databases that capture bioactive content. We focused particularly on those that specify relationships between compounds and their protein targets. Our stringent filtering produced lower unique compound numbers than those reported for individual databases and thereby facilitated standardised comparisons of content. The resultant matrix shows the pairwise comparison of each database and selected subsets. Overall, this showed an unexpected degree of non-overlap, thereby emphasising the complementarity gained from combining public and commercial sources. This conclusion is supported by a Venn-type analysis of GVKBIO, WOMBAT (both commercial) and PubChem (public). These databases show not only overlap but also unique bioactive content in each case because of their different strategies for source selection and data collection

Complementarity between public and commercial databases: new opportunities in medicinal chemistry informatics

<p><strong>Abstract</strong></p> <p>The last two years have seen a dramatic expansion in public cheminformatics, as exemplified by the approximate five-fold growth of PubChem from over 50 contributing data sources. Consequently, medicinal chemists who were hitherto limited to commercial databases now also have access to public sources that they can download and/or query directly over the Web. The range of public sources, particularly where they link out to structured bioinformatic and biological data, already offer utilities that have no commercial equivalent. This work reviews compound content comparisons between selected public and commercial databases that capture bioactive content. We focused particularly on those that specify relationships between compounds and their protein targets. Our stringent filtering produced lower unique compound numbers than those reported for individual databases and thereby facilitated standardised comparisons of content. The resultant matrix shows the pairwise comparison of each database and selected subsets. Overall, this showed an unexpected degree of non-overlap, thereby emphasising the complementarity gained from combining public and commercial sources. This conclusion is supported by a Venn-type analysis of GVKBIO, WOMBAT (both commercial) and PubChem (public). These databases show not only overlap but also unique bioactive content in each case because of their different strategies for source selection and data collection.</p