Recore: Instant 3-D scaffold hopping using replacement fragments

COMP 84

Christian Lemmen, Carsten Detering, detering@biosolveit.de, Marcus Gastreich, marcus.gastreich@biosolveit.de, and Peter R. Oledzki, peter.oledzki@biosolveit.de. BioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, Germany
Recore, a 3D ligand scaffold replacement tool generates new ligand cores within a few seconds. It is an ideal solution for deriving new lead structures from existing ones which may be patent protected or otherwise unusable.Given a user-defined ‘core', Recore identifies the geometrically best possible replacement from a 3D fragment database. We used Recore to define 3D fragment sets based on either crystal structures or generated conformers of drug-like molecules. Recore identifies suitable fragments by shredding according to RECAP-type rules for high likelihood of synthetic accessibility. Recore was applied to pharmaceutically relevant targets using the bioactive conformations of known binders. Results show that Recore is able to replace a central unit and jump from one chemical series to another while preserving the position of the side-chains. Other known actives in their bioactive conformation were identified and additional pharmacophore-constraints further helped guide the search towards relevant solution sets.