Correlation of binding site properties with chemistries used for generation of ultra-large virtual libraries.

Although the size of virtual libraries of synthesizable compounds is growing rapidly, we are still enumerating only tiny fractions of the drug-like chemical universe. At the same time, our ability to mine these newly generated libraries also lags their growth. That is why fragment-based approaches that utilize on-demand virtual combinatorial libraries are gaining popularity. These à la carte libraries utilize synthetic blocks that have been shown to be effective binders in parts of target protein pockets. There is, however, no data on the potential impact of the chemistries used for making on-demand libraries on the hit rates during virtual screening. There are also no rules to guide in selection of these synthetic methods for libraries production. We have used the SAVI (Synthetically Accessible Virtual Inventory) library, constructed using 53 reliable reaction types (transforms), to test for correlations between these chemistries and docking hit rates for 39 well- characterized protein pockets. The data shows that the hit rate depends on the chemistry used and that chemistry selection can be optimized based on pocket properties.