Combinatorial chemistry has emerged as very powerful tool for drug discovery. However, increasing the library size does not necessarily result in many new hits and lead compounds. Because the number of thinkable organic compounds is almost infinite, there are quest arises for a biologically validated starting point in library synthesis. Natural products that bind to certain protein domains might provide such biologically validated starting points. Recent discoveries reveal that three-dimensional folds of different protein domains are often similar and that the number of distinct protein domains and families is fairly limited.
Based on this it can be envisioned that natural products that bind to one member of a protein domain family can be used as a guiding principle to design ligands that bind to other members of the same protein domain family. This proposal focuses on the natural product tetrahydrolipstatin (THL) that binds to gastric and pancreatic lipase, which have high three dimensional similarity with the C dc25A phosphatase. This phosphatase has an important role in progression of the cell cycle and is thus a target for anti-cancer drug development. Combinatorial libraries inspired by the THL core structure will be assembled and screened for Cdc25A phosphatase activity, which will ultimately lead to a new generation of anti-cancer drugs.
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