Following suggestions by Brown et al. and Gao and Coley we show that the synthetic accessibility can be increased significantly by the combined use of Walters rd filters code and a score modifier based on a heuristic synthetic accessibility (SA) score (GA+Filter+SA). However, this also leads to a drop in the number of molecules with scores better than known binders of between 22% (BCD) and 95% (CM). The GA+Filter+SA approach thus identifies between roughly 500 and 6000 structurally diverse (Table and Figure ) molecules with scores better than known binders by screening a total of 400,000 molecules starting from 8000 randomly selected molecules from the ZINC database. However, screening 250,000 molecules from the ZINC database identifies significantly more molecules with better docking scores than known binders, with the exception of CM, where the conventional HTVS approach only identifies 60 compounds compared to 511 with GA+Filter+SA (Table ). The known binders for the remaining targets have relatively low docking scores of less than -7.0. In the case of β 2 AR and DDR1 the GA+Filter+SA approach finds significantly more molecules with docking scores lower than -9.0 and -10.0. The GA+Filters+SA docking methodology is thus effective in generating a large and diverse set of synthetically accessible molecules with very good docking scores for a particular target. However, for targets such as CM that predominantly binds charged ligands this approach will need to correct for unphysical protonation states by, for example, including additional filters or adding a term to the score that penalizes large deviations from empirically estimated pK a values.