A limitation to this study surrounds the inevitably incomplete nature of freely available Reference compound datasets. To help corroborate our results, we encourage owners of complete drug discovery project databases to examine the NP properties of optimised leads and candidate drugs versus others synthesised, an approach that does not require disclosure of proprietary structures in publication. Similarly, higher NP character of identified hits versus compound screening collections, if seen, could help shed light on the presence of 'dark' chemical matter. Nevertheless, we believe that the results showing Clinical NP enrichment based on published compound data are sufficiently positive to warrant a greater focus on the application of NP properties and fragments in compound design.