Specific Methyl Group Protonation for the Measurement of Pharmacophore‐Specific Interligand NOE Interactions

Pharmacophore signature at glance: INPHARMA NOE interactions can be measured between two ligands that bind competitively to a common macromolecular receptor, and can be interpreted quantitatively to derive the binding mode of the two ligands. This approach relies on computationally demanding full relaxation matrix calculations. Here we demonstrate that the INPHARMA NOEs measured in the presence of a selectively-protonated receptor (see figure) can be interpreted in a semiquantitative way to discriminate between binding poses, thus relieving for the need of demanding computations.