The here named evolutionary docking belongs to self-supervised generation methodologies that bypass the screening of large chemical data banks to detect new protein ligands. In the present particular case, evolutionary docking was used to augment the repertoire of specific ligands by targeting a defined docking-cavity. Specificity was theoretically increased by adding low molecular weight and hydrophobic criteria aiming to reduce off-target effects. The brodifacoum chemotype was selected as the initial parent molecule from which randomly generate multiple children derivatives, because is among the most potent rodenticides due to its highly hydrophobic tail (LogP = 8.0, penetrating the VKORC1 binding central cavity). Additionally, the brodifacoum chemotype shares hydroxycoumarin heads similarly common to warfarine, coumatetralyl, bromadiolone, difenacoum, difethialone, and flocoumafen. Furthermore, a crystallized brodifacoum-binding model has been recently elucidated in human VKORC1 (Figure ). Nevertheless, because its high hydrophobicity may contribute to unespecificity (by binding to any hydrophobic protein surfaces), and therefore increase off-target effects to any proteins from other biological species, reduction of hydrophobicity was also included among selective criteria during evolution.