ADDRESSING THE CHALLENGES POSED BY COMBINATORIAL CHEMISTRY - 3D DATABASES, PHARMACOPHORE RECOGNITION AND BEYOND

The flow of information in combinatorial chemistry is much like that w hich medicinal chemists have traditionally faced; however, the speed a nd quantity of that flow is much greater. In traditional chemistry, co mputational tools have been applied essentially as a replacement for D reiding models; with combi-chem, the use of computational tools now be comes compelling. In our environment, the primary focus is less on the use of combi-chem in the development of universal libraries for scree ning, and more on its use in the development of targeted libraries. He nce, the four primary challenges we face are: (1) gaining an understan ding of the structure-activity relationship (SAR), (2) using that unde rstanding in the iterative design of new targeted libraries, (3) incor porating any structural data into that iterative design process, and ( 4) registering the compounds produced by combi-chem into a database. F or computational tools to be effective, they must address these challe nges more quickly and more accurately than the combi-chemist is able t o achieve independently, i.e, high-quality answers must be developed i n less than a few days. We describe how the first challenge may be add ressed by pharmacophore recognition tools (Catalyst, DANTE), how the s econd and third may be addressed by 3D database searching, and how the fourth may be addressed by 'virtual chemistry' using databases of com pounds and tables of reactions which may be applied to those compounds .