FlexNovo: Structure-based searching in large fragment spaces

We present a new molecular design program, FLExNovo, for structure-based searching within large fragment spaces following a sequential growth strategy. The fragment spaces consist of several thousands of chemical fragments and a corresponding set of rules that specify how the fragments can be connected. FLExNovo is based on the FLEXX molecular docking software and makes use of its incremental construction algorithm and the underlying chemical models. Interaction energies are calculated by using standard scoring functions. Several placement geometry, physicochemical property (drug-likeness), and diversity filter criteria are directly integrated into the "build-up" process. FLExNovo has been used to design potential inhibitors for four targets of, pharmaceutical interest (dihydrofolate reductase, cyclin-depend- ant kinase 2 cyclooxygenase-2 and the estrogen receptor). We 1 have carried out calculations using different diversity parameters for each of these targets and generated solution sets containing up to 50 molecules. The compounds obtained show that FLEXNovo is able to generate a diverse set of reasonable molecules with drug-like properties. The results, including an automated similarity analysis with the Feature Tree program, indicate that 1 FLExNovo often reproduces structural motifs as well as the corresponding binding modes seen in known active structures.