Bioconformational modulation of a thymidine kinase enzyme ligand through F⋯HO intramolecular hydrogen bond

While the induced-fit of a ligand towards an enzyme is pivotally dictated by intermolecular hydrogen bonds between the small molecule and amino acid residues in the binding site, the role of intramolecular hydrogen bond as contributing interaction for a bioactive conformation is not well understood. This work reports a theoretical conformational analysis of a thymidine kinase enzyme ligand (NMF) that is prone to experience an F⋯HO intramolecular hydrogen bond, inside and outside the biological binding site. This interaction stabilizes the most favorable conformations of NMF in the gas phase and, although it can be disrupted in a biological environment due to intermolecular hydrogen bonds in some cases, these interactions are competitive in other systems. Therefore, an intramolecular hydrogen bond can affect the conformational likeliness most related to the bioactivity. Moreover, isolated conformations governed by this interaction cannot be unequivocally used to generate molecular descriptors in 3D-QSAR (Quantitative Structure-Activity Relationships), since the bioactive conformation may not be determined only by intramolecular interactions.