PMC:7594251 / 62794-64111 JSONTXT

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Diffusion-based NMR spectroscopy has advantages in ligand based screening applied to drug discovery. For example, Diffusion Ordered Spectroscopy (DOSY) does not require prior separation/purification of the ligand/target solution [298]. Diffusion based NMR allows simultaneous determination of diffusion coefficients in multicomponent systems containing large molecules (i.e., proteins) and possible binding partners (i.e., small drug compounds) [285], and no special labeling or contrasting agents are required, though their use is not exclusively inhibited (for an example of the use of labeled compounds in diffusion NMR spectroscopy, see [299]). A problem occurs when there is significant chemical shift overlap between the binding molecule signals and the target. This situation makes it hard to distinguish the NMR signals [300], and the calculations typically assign an intermediate value to the diffusion rate (i.e., one gets a smear). Multidimensional diffusion NMR pulse sequences are available [301], which may help resolve spectral overlap in 1D experiments [300]. Another issue is that molecules in chemical databases may have generally low solubility [302,303]. Low solubility decreases the overall signal intensity and therefore makes accurately measuring diffusion experiments far more difficult [304].