5. tPSA ≤ 90 Å 2 : this component is included in the CNS MPO algorithm and is enforced to be in an interval in agreement with CNS penetration. The interval was also specifically desired by Patel et al. See Supporting Information Fig. for the Scoring Function transformation. as the binding site geometry is most compatible with a planar ring present in the core scaffold. See Supporting Information Fig. for the Scoring Function transformation. show the interactions formed by the reference ligand and generated ligand, respectively. The generated molecule retains the Cys193 interaction as enforced by the docking constraint and is predicted to form an additional hydrogen-bond interaction with Gln195. The extensive overlap between the binding poses of the generated ligand and the reference ligand supports plausibility.