While the first group mainly focuses on the differences at the hydrophobic site, the compounds in the second group share the same isopropyl group at the hydrophobic site but differ at other functional site(s) (Figure ). Compound L2 is in both of the groups, and is one of the best binders in the first group. The grouping indeed represents the common lead optimisation steps: optimising one functional position of the lead to find more promising compounds, and then adding/changing functional groups at other positions.