2604.01059 Substituent Additivity in SAR Landscapes Is Target-Specific: A Dual-Null Matched Molecular Pair Square Permutation Analysis Across Nine ChEMBL Targets
The additivity assumption — that the potency effects of two independent structural modifications combine linearly — underpins free energy perturbation calculations, multi-parameter QSAR, and routine medicinal chemistry extrapolation. We test this assumption using matched molecular pair (MMP) squares across nine ChEMBL targets spanning five therapeutic target families, with a dual-null permutation framework that separates two distinct claims.