The observed Clinical NP fragment preferences in the data set (Figures and) are intriguing and suggest specific fragments and combinations that could take priority in compound design. An important point is that any specific NP fragments contained in Clinical compounds which were generally introduced at late stages in the lead optimisation processes, could appear 'enhanced' in Clinical versus comparative Reference compounds. An example is oxetane, a relatively new entry to the repertoire which is enriched in Clinical compounds (Figure , 8 th entry in 5 th row). This effect would be less likely to be seen for NP fragments present in starting hit structures. Quantifying the impact of these aspects is not practicable in the current dataset. The narrowing of successful design options using specific NP fragments, which occurs as lead optimisation progresses, is consistent with a 'natural selection' hypothesis.