Abstract
19F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the target protein, useful information can be obtained on not only the binding pose but also the dynamics of ligand-protein interactions. These applications of 19F-NMR will be illustrated in this review with studies from our fragment-based drug discovery campaigns against protein targets in parasitic and infectious diseases.
Highlights
With a decline in the number of new FDA-approved drugs reaching the clinic each year [1], in particular in the area of new antibiotics [2], new approaches to the development of therapeutic leads are needed
367 resonance, similar to that caused by the peptide ligands (Figure 3d). This result suggests that members of this series of elaborated fragments displace the DII loop in much the same way as the peptide ligands do, it should be noted that the ligand shown in Figure 3d is a 2-aminothiazole, which we have shown in a separate study is a promiscuous binder that is not necessarily suitable as a starting point for an Fragment-based drug discovery (FBDD) campaign [54]
Having established the sensitivity of 19F-NMR in detecting ligand binding to the hydrophobic cleft of Apical Membrane Antigen 1 (AMA1), we further explored the utility of fluorinated R1 probe in a 19F-NMR
Summary
With a decline in the number of new FDA-approved drugs reaching the clinic each year [1], in particular in the area of new antibiotics [2], new approaches to the development of therapeutic leads are needed. A successful FBDD program requires a biomolecular target that is relatively stable and can be produced in milligram quantities, a well-constructed fragment library [13], one or more robust biophysical screening methods [14], and access to medicinal chemistry expertise to develop promising hits. Important is high-quality structural information on the binding pose(s) of elaborated fragments as this is required to guide medicinal chemistry optimization While this information can be obtained using X-ray crystallography [15,16], there are numerous examples where visualization of the bound ligand in this way is not feasible because crystallization of the ligand-target complex is too slow or fails completely. 19 F resonances are highly sensitive to chemical environment, with a chemical shift range spanning several hundred ppm
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