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Publication Abstract from PubMed

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.

Mathematical and Structural Characterization of Strong Non-additive SAR Caused by Protein Conformational Changes.,Gomez L, Xu R, Sinko W, Selfridge B, Vernier WF, Ly K, Truong R, Metz M, Marrone T, Sebring K, Yan Y, Appleton B, Aertgeerts K, Massari E, Breitenbucher JG J Med Chem. 2018 Aug 2. doi: 10.1021/acs.jmedchem.8b00713. PMID:30070482^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.