What has caused the overall separation of PNP abundance in Clinical and Reference compounds published after 2008? Developments in the late 1990s to early 2000s such as the maturity of compound screening collection enhancements and multiparameter lead optimisation, may be contributory factors. In the same time frame, the increased attention paid to physical property control is an additional factor: higher Fsp3 and complexity, with lower carboaromatic ring count are evident in Clinical compounds versus Reference compounds (Figure ) and these trends are consistent with increased NP character.