Fragment-based drug discovery: what has it achieved so far?

Fragment-based drug discovery has proved to be a very useful approach particularly in the hit-to-lead process, providing a complementary tool to traditional high-throughput screening. Although often synonymous with fragment screening, fragment-based drug discovery is a far wider area covering high-throughput screening, fragment screening and virtual screening efforts. The unifying feature of fragment-based drug discovery is the low molecular weight of the hit rather than the approach it originates from.

Development of a combined protein and pharmacophore model for cytochrome P450 2C9.

A combined protein and pharmacophore model for cytochrome P450 2C9 (CYP2C9) has been derived using various computational chemistry techniques. A combination of pharmacophore modeling (using 31 metabolic pathways for 27 substrates), protein modeling (using the rabbit CYP2C5/3 crystal structure), and molecular orbital calculations was used to derive a model that incorporated steric, electronic, and chemical stability properties. The initial pharmacophore model (based on a subset of 17 metabolic pathways for 16 substrates) and the protein model used to construct the combined model were derived independently and showed a large degree of complementarity.