BIBuilder: Exhaustive Searching for De Novo Ligands

The de novo design program BIBuilder has been developed for structure-based as well as ligand-based design. Incremental growth allows for the de novo design of novel molecules with putative bioactivity. In addition, linking between existing fragments enables scaffold hopping tasks. A RECAP-based retrosynthetic fragment connection protocol yields ligands that are synthesizable. An exhaustive fragment search protocol assures that known ligands are always found if all necessary fragments exist in the database of building blocks. To make an exhaustive search possible, a strategy of connecting tens of thousands of unique fragments with only three growth or linking steps is adopted resulting in the generation of up to 10(16) possible compounds with up to 10(21) conformations. Ligands are scored by shape and pharmacophore matches that can be individually weighted. Final hits are evaluated through customizable scoring functions. Estrogen receptor, COX-2, renin, and NNRTI examples illustrate the performance of BIBuilder in different tasks such as structure-based or ligand-based growing and linking. Not only are known ligands reproduced in all test cases but a number of interesting alternative scaffolds and ligands have been found.