Synthon-Based Strategies Exploiting Molecular Similarity and Protein–Ligand Interactions for Efficient Screening of Ultra-Large Chemical Libraries

The rapid expansion of ultralarge chemical libraries has revolutionized drug discovery, providing access to billions of compounds. However, this growth poses relevant challenges for traditional virtual screening (VS) methods. To address these limitations, synthon-based approaches have emerged as scalable alternatives, exploiting combinatorial chemistry principles to prioritize building blocks over enumerated molecules. In this work, we present exaScreen and exaDock, two novel synthon-based methodologies designed for ligand-based and structure-based VS, respectively. In the former case, synthon selection is guided by the 3D hydrophobic/philic distribution pattern in conjunction with a specific synthon alignment protocol based on a quadrupolar expansion over the atoms that participate in the linking bonds between fragments. On the other hand, accommodation to the binding site under a geometrically restrained docking of synthon-based hybrid compounds is used in the selection of the optimal synthon combinations. These strategies exhibit comparable performance to the search performed using fully enumerated libraries in identifying active compounds with significantly lower computational cost, offering computationally efficient strategies for VS in ultralarge chemical spaces.