Mathematical and Structural Characterization of Strong Non-additive SAR Caused by Protein Conformational Changes.

In medicinal chemistry, additivity-based SAR analysis rests on three assumptions: (1) con-sistent binding pose of the central scaffold, (2) no interaction between the substitutions, and (3) a relatively rigid binding pocket in which the two substitutions act independently. Previously, non-additive SAR have been documented in systems that deviate from the first two assump-tions. Interestingly, protein structural change upon ligand binding, through induced fit or con-formational selection, although a well-known phenomenon that invalidates the third assump-tion, has not been linked to non-additive SAR conclusively. Here, for the first time, we show clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct sub-pocket, and contribute to strong non-additive SAR between two otherwise distant R groups.