A fragment-based de novo application in the context of the active site
C. Detering, H. Claußen, and Marcus Gastreich
FlexNovo is a molecular design program for structure-based de novo searching in large fragment spaces following a sequential growth strategy. Having the active site as structural information, it uses fragment spaces as input that consist of several thousands of chemical fragments and a corresponding set of rules, which primarily specifies how the fragments can be connected with each other. Synthesizability can be ensured by several placement geometry, drug-likeness and diversity filter criteria that are directly integrated in the build-up process.
FlexNovo can be used for fragment expansion, e.g., starting from an Xray structure that has been produced in a fragment screen. Or it can be used entirely in a de novo fashion where the algorithm places fragments arbitrarily in the pocket and then grows the compound from the most promising ones.
We demonstrate the performance of FlexNovo on a few relevant medicinal chemistry projects.