2. Linker Number of Rings: reward is only given if the linker contains exactly one ring. amide bonds that modulate the linker flexibility and rigidity which the authors attribute to its binding potency. Experiment 1: Fragment Linking. Fusco, Brear, et al. applied a fragment linking strategy (Fig. ) to design casein kinase 2 inhibitors for the alpha catalytic site (CK2α). CK2 is overexpressed in cancers and causes apoptosis evasion, leading to poor cancer prognosis and is therefore a therapeutic target of interest. Fig. shows the fragment linking strategy envisioned by Fusco, Brear, et al. The gray fragment binds by forming hydrogen-bond interactions with Lys68 and Asp175 and the green fragment binds primarily through hydrophobic interactions (Fig. ). The difference in the binding modes of the constituent fragments were judged to be suitable for linking. Following this strategy, a potent and selective CK2α inhibitor (CAM4066) was discovered that retains the important Lys68 hydrogen-bond interaction (Fig. ). CAM4066 was demonstrated to exhibit in vivo efficacy and is thus an example of a successful fragment linking campaign. In this section, we adopt the fragment linking strategy devised by Fusco, Brear, et al. (Fig. ) and task Link-INVENT with generating plausible linked molecules that retain the Lys68 hydrogen-bond interaction. Moreover, while Fusco, Brear, et al. exclusively evaluated linear linker ideas, we allow Link-INVENT to explore linkers with rings and branching (to a certain extent). Correspondingly, we devise a Scoring Function composed of the following components: