Conventional lead discovery approaches, the identification of scaffold displaying a desired biological activity, rely on the synthesis of building blocks and their transformation into combinatorial libraries consisting of large numbers of distinct new compounds, which are usually characterized before subjecting them to high-throughput screening assays. Although researchers in industry and academia have invested heavily in optimizing and streamlining such discovery approaches for some time, now they have been disappointed with their success. The decline in the rate of submission and introduction of new drug candidates over the last 10 years is alarming and provokes questions about the effectiveness of the existing approaches to drug discovery. One of the research areas of the Manetsch laboratory focuses mainly on lead discovery and optimization using synthetic chemistry in close conjunction with liquid chromatography with mass spectrometry (LC/MS). We are especially interested in the development of straightforward strategies for fragment-based lead discovery and optimization using the protein of interest to assemble its own high-affinity bidentate ligand from a library of complimentary reacting fragments. In comparison to conventional fragment-based discovery technologies, the identification of hit fragments and their evolution into bidentate ligands is combined in one single step. We hypothesize that this directs the medicinal chemist to focus synthetic resources solely on biologically relevant compounds at the earliest possible stages of PPIM development.
Namelikonda, N. K.; Manetsch, R. Chem. Commun. (Camb).2012, 48, 1526–1528.
Kulkarni, S. S.; Hu, X.; Doi, K.; Wang, H.-G.; Manetsch, R. ACS Chem. Biol. 2011, 6, 724–732.
Hu, X.; Sun, J.; Wang, H.; Manetsch, R. J. Am. Chem. Soc. 2008, 130, 13820–13821.