Abstract: This disclosure provides for modular synthon-based screening for rapid drug discovery. Such screening includes initially docking a pre-built set of fragment-like compounds representing library reaction scaffolds and corresponding synthons. Best selected scaffold and synthon combinations from the initial docking are used to enumerate a further library, which is screened again to produce fully enumerated compounds. Such an iterative approach focuses on a subset of synthons at each screening, thereby reducing the combinatorial chemical space for docking and facilitating more rapid drug discovery.