Mathematical and Structural Characterization of Strong Nonadditive Structure–Activity Relationship Caused by Protein Conformational Changes

In medicinal chemistry, accurate
prediction of additivity-based
structure–activity relationship (SAR) analysis rests on three
assumptions: (1) a consistent binding pose of the central scaffold,
(2) no interaction between the R group substituents, and (3) a relatively
rigid binding pocket in which the R group substituents act independently.
Previously, examples of nonadditive SAR have been documented in systems
that deviate from the first two assumptions. Local protein structural
change upon ligand binding, through induced fit or conformational
selection, although a well-known phenomenon that invalidates the third
assumption, has not been linked to nonadditive SAR conclusively. Here,
for the first time, we present clear structural evidence that the
formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic
site reduces the size of another distinct subpocket and contributes
to strong nonadditive SAR between two otherwise distant R groups.