Systematic Exploration of Activity Cliffs Containing Privileged Substructures.

The privileged substructure (PS) and activity cliff (AC) concepts are popular in pharmaceutical research. PSs have been empirically identified as preferred building blocks for target-class-directed generation of active compounds. Although some PSs are controversially viewed, they continue to receive much attention in drug discovery. ACs are formed by structurally similar active compounds with large potency differences and thus capture structure-activity relationship (SAR) discontinuity and reveal SAR determinants. So far, the PS and AC concepts have not been investigated in context. We have systematically explored ACs formed by compounds containing different PSs (PS-ACs). Such ACs were frequently identified in different series of compounds. PS-ACs were thoroughly characterized and compared to ACs formed by other compounds. The analysis revealed differences in AC formation between PSs. For example, individual PSs with an unusually high proportion of AC-forming compounds were identified. Furthermore, PS-AC network analysis identified clusters of ACs containing the same PS in different compound structure contexts with activity against different targets. From such PS-AC clusters, target-specific SAR information for PSs in different structural environments can be extracted.