The use of ligand-based predictive models as scoring functions for de novo molecule optimisation can however lead to sub-optimal behaviour. Predictive models must have a broad enough applicability domain to perform expectedly given the broad scope of initial de novo molecules [17], and generative model optimisation can lead to exploitation of predictive model limitations . In contrast, structure-based scoring functions have been shown to improve de novo molecule diversity, and coverage of bioactive chemical space . Therefore, we design a third set of objectives utilising structure-based principles (as with the other objectives a diversity filter is also used):