| METHOD |
Scaffold-based drug design disclosed Scaffold-based drug design, a rapid route to drug leads, has been used quietly for years, but now main author and coworkers have described it in the literature for the first time. The technique is midway between high-throughput screening (HTS) and fragment-based design. In HTS, fast biochemical assays are used to test large numbers of druglike compounds for activity, and the best "hits" are optimized to create drug leads. In fragment-based design, slower biophysical methods such as NMR and crystallography are used to screen small numbers of very small building blocks for affinity to target sites, and hits are combined and built up to create drug leads. In scaffold-based design, HTS-type assays are used initially to screen intermediate numbers of scaffolds (larger size than fragments but smaller than druglike compounds). The hits are then validated and optimized by high-throughput cocrystallography of ligand-target pairs. Main author and coworkers demonstrate the technique's robustness by using it to identify novel selective phosphodiesterase inhibitors with only two rounds of synthesis and seven structural analyses. |
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