Consequently, the solution space is much narrower. It is important to note, however, that the objective of the scaffold hopping experiment is not strictly to propose novel cores that dock better than the initial inhibitor (Fig. ). Patel et al. note that their initial inhibitor, while potent, exhibits high in vivo clearance. Therefore, an inhibitor with sufficient binding affinity and good CNS penetration could achieve in vivo efficacy. The narrower solution space in the scaffold hopping experiment is further supported by Fig. where the absolute counts of unique Bemis-Murcko scaffolds is less than the fragment linking experiment. This is not a limitation of Link-INVENT but rather the nature of the MPO objective. Nonetheless, the absolute counts for the generated scaffolds is still high and demonstrates Link-INVENT samples from diverse minima. Similar to the fragment linking results, minimal overlap between replicate runs show that replicate experiments explore different areas in chemical space (Fig. ). The plausibility of the proposed scaffolds was investigated by comparing their binding poses with the reference ligand. Fig. shows the binding pose of an example top scoring molecule (based on satisfaction of the composite Scoring Function) superimposed with the reference ligand (see Supporting Information Fig. for more examples). Firstly, the proposed scaffold features planar aromatic rings, as enforced by the Scoring Function, and as desired by Patel et al. Secondly, the Cys193 hydrogen-bond interactions are retained, as enforced by the docking constraint. The proposed ligand is predicted to form an additional hydrogen-bond with Gln195, owing to the hydrocarbon chain that extends the spatial occupancy of the overall molecule (Fig. ). This suggests that the application of a docking constraint can guide the Link-INVENT agent towards 3D structural awareness, learning to exploit the binding site geometry and electronics. Lastly, the binding poses of the generated ligand and the reference ligand overlap significantly, supporting plausibility. Taken together, the results in this section demonstrate the flexibility of the Link-INVENT Scoring Function to optimize relatively complex MPO objectives and that the agent learns to propose plausible chemical ideas. pomalidomide which is a cereblon (CRBN) binding ligand (Fig. ). The resulting ternary complex would undergo ubiquitination and lead to targeted dual degradation of Bcl-2 and Mcl-1. Due to challenges in obtaining crystal structures as a basis to form hypotheses on optimal linker lengths, PROTACs linker design has mostly been empirical. Wang et al. adopt an iterative SAR approach to investigate the effect of linker length on Bcl-2 and Mcl-1 dual degradation, whereby a linker too short would cause steric clash and prevent the formation of the stable ternary complex and a linker too long could result in too much conformational entropy to overcome. Following this approach, Wang et al. successfully transform a low-affinity and non-selective ligand for Bcl-2 and Mcl-1 into PROTACs stabilized via protein-protein interactions (PPIs) and show potent and selective dual degradation in vitro. 2) Linker Length Ratio = 100 this component prevents linker branching.