Fragment Shuffling: An Automated Workflow for Three-Dimensional Fragment-Based Ligand Design

Fragment-based approaches display a promising alternative in lead discovery. Herein, we present the automated fragment shuffling workflow for the identification of novel lead compounds combining central elements from fragment-based lead identification and structure-based de novo design. Our method is based on sets of aligned 3D ligand structures binding to the same target or target family. The implementation comprises three different ligand fragmentation methods, a scoring scheme assigning individual scores to each fragment, and the incremental construction of novel ligands based on a greedy search algorithm guided by the calculated fragment scores. The validation of our 3D ligand design workflow is presented on the basis of two pharmaceutically relevant drug targets. A retrospective study based on a selected protein kinase data set revealed that the fragment shuffling approach realizes extended results compared to the well-known BREED technique. Furthermore, we applied our approach in a prospective study for the design of novel non-peptidic thrombin inhibitors. The designed ligand structures in both studies demonstrate the potential of the fragment shuffling workflow.