Impacts of stereochemistry and activity cliffs in quantitative structure-activity relationships (QSAR) models

Activity cliffs¶

Activity Cliffs (ACs) were generally defined as pairs of structurally similar compounds showing a marked difference in potency. The existence of ACs directly defies the intuitive idea that chemical compounds with similar structures should have similar activities, often referred to as the molecular similarity principle, and highlights the remarkable specificity of their interaction with biological systems (e.g., proteins). As such, ACs received strong attention in computational chemistry and drug design Stumpfe et al. 2019, Tilborg et al. 2022.

Activity cliff can be defined based on the substructure of molecules or the similarity computed by molecular representations.

The figure below shows selected examples of activity cliffs from Stumpfe et al. 2019.

Stereoisomerism¶

Stereoisomerism refers to the phenomenon where molecules with the same molecular formula and connectivity (i.e., the same number and type of atoms bound in the same sequence) differ in the spatial arrangement of their atoms, leading to the existence of stereoisomers. Stereoisomers are a type of isomer where the differences arise not from the sequence of bonds but from the orientation of the atoms in three-dimensional space.