Rule-Defined Multitopology PEG Ligand Library for Virtual Screening

Abstract Poly(ethylene glycol) (PEG) is widely used in drug delivery, primarily as a passive protective component, whereas active targeting typically relies on additional, structurally complex ligands. Developing PEG as a ligand with targeting potential could simplify the architecture of targeted nanomedicines; realizing this concept first requires treating PEG topology as a ligand-scaffold design variable and establishing a unified multitopology structural resource. Using a shared local assembly grammar and topology-specific rules, we constructed a rule-defined PEG ligand 2D master library spanning seven topology classes; the generated view contains approximately 123 million unique structures, and the default-retained view contains approximately 50 million unique structures. The library extends the represented PEG ligand space beyond linear chains to include branched, multiarm, ring-constrained, and multicyclic regions, thereby providing a traceable 2D structural basis for downstream virtual screening.