Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein...

Compound libraries were designed to target specifically the ATP cofactor-binding site in protein kinases by combining knowledge- and diversity-based design elements. A key aspect of the approach is the identification of molecular building blocks or scaffolds that are compatible with the binding site and therefore capture some aspects of target specificity. Scaffolds were selected on the basis of docking calculations and analysis of known inhibitors. We have generated 75 molecular scaffolds and applied different strategies to compute diverse compounds from scaffolds or, alternatively, to screen compound databases for molecules containing these scaffolds. The resulting libraries had a similar degree of molecular diversity, with at most 12% of the compounds being identical. However, their scaffold distributions differed significantly and a small number of scaffolds dominated the majority of compounds in each library.