Retrosynthetic Analysis-Aware Fragment Linking for Structure-Guided Ligand Extension

Synthetic accessibility is a key issue in the current compound generation. Unlike conventional approaches that assess synthetic accessibility after compound generation, the fragment-based method proposed in this study links the fragments in the reverse direction of the retrosynthesis analysis guaranteeing the synthetic accessibility. We developed a LigX, a Python module that incorporates this concept into the structure-based compound generation and applied it for the generation of nuclear receptor-binding SET domain-containing 2 (NSD2)-PWWP domain binders. The LigX generated structurally diverse compounds with higher synthetic accessibility. The effectiveness of our method was demonstrated through the chemical synthesis of one of the generated compounds, which showed a moderate binding affinity for recombinant NSD2. The results presented here suggest that by considering the difference between fragments suitable for compound generation and those used in chemical synthesis, it is possible to generate compounds with improved synthetic accessibility.