Project Approach Impact DPP-IV Filling a lipophilic pocket Affinity increase while balancing polarity FABP 4/5 Targeting specific residue differences in the binding site Affinity and selectivity increase Cathepsin S/L Assessment of electrostatic complementarity of protein and ligand. Visualization of halogen bonding potential Affinity and selectivity increase Β-Tryptase Scaffold hopping Alternative scaffold BACE1 Scaffold hopping Solubility increase, alternative scaffold PDE 10A Targeting binding site hotspots identified from multiple crystal structures, Calculation of torsion energy potentials Affinity increase,Prioritization of alternative scaffolds HSL Hypothesis derived from homology model Novel scaffolds with potential for improved PK
properties GPBAR1 Hypothesis derived from homology model Targeted introduction of solubilizing group L-CPT1 Bioactive shape hypothesis Prioritization of scaffolds SSTSR Sequence-based binding site similarity as a basis for focused screening (“chemogenomics”) Identification of druglike hits