Structure-guided fragment linking algorithm enables chemically feasible ligand design with predicted binding modes

Fragment-based drug discovery offers an efficient strategy for exploring chemical space and identifying novel therapeutics. However, the rational design of linkers connecting promising fragments remains a significant bottleneck, with existing computational methods suffering from limited synthetic accessibility and inadequate preservation of fragment binding orientations. We developed CRET (Chemically Reasonable Tethering), a unified computational framework that automates the process of fragment linking by generating specific 3D conformations of compounds directly within the binding pocket. The algorithm identifies linkers that match the molecular context of both fragments and applies chemically plausible transformations to ensure high synthetic accessibility. The resulting molecule is then aligned with the fragment poses using template docking. Comprehensive benchmarking against established generative models demonstrates CRET's superior performance in the generation of unique, high-quality linkers, predicted binding pose accuracy, and preservation of fragment orientations. The developed algorithm was tested on challenging ligand classes such as PROTACs and macrocycles, yielding satisfactory results in terms of the generated structures within relevant protein binding sites. The strong results and the ability of the algorithm to handle complex ligands position CRET as a valuable tool for advancing structure-based drug discovery efforts.