A set of tuberculosis fragment inhibitors has been discovered by mass spectrometry. The method is based on the observation of protein-ligand complexes by mass spectrometry. 1 These fragments may compete for common binding sites on the target protein or bind at different sites. Mass spectrometry enables identification of ternary complexes in which two ligands bind to different sites of a target. 2-3
For a specific target, the result (P+L1) + (P+L2) indicates binding to the same site (competitive), while the result (P+L1) + (P+L2) + (P+L1+L2) shows that L1 and L2 bind to different sites (non-competitive). Compound design relies on using a number of competitive fragments linked to a non-competitive fragment. Therefore, the structures of these fragments will be modified using synthetic methods to enhance their activities and produce novel inhibitors.
References:
1. Chan D, Whitehouse A, Coyne A, Abell C. Essays In Biochemistry 2017.
2. Pedro L, Quinn R. J. Molecules 2016; 21 (8); 984.
3. Ockey D. A., Dotson J. L., Struble M. E., Stults J. T., Bourell J. H., Clark K. R., Gadek T. R. Bioorganic & medicinal chemistry 2004; 12 (1); 37-44.