Leveraging general molecular fragments to expand the design space of metal-organic polyhedra

The discovery of functional reticular materials is dependent on optimising the organic building unit to achieve precise chemical and structural properties. However, experimentally characterised chemical building units (CBUs) are only a small fraction of the possible design space, and as such, computer-aided design based on datasets of known reticular materials have fundamental limitations in chemical diversity. Here, we present a general workflow for extracting, analysing, and recombining molecular fragments from large, chemically diverse datasets to systematically expand the accessible organic CBU design space. Using the ChEMBL36 database as a case study, we generate a library of 12 387 unique fragments through filtering, fragmentation, and ontology-driven classification. These fragments are recombined to enumerate a dataset of 44.8 million CBUs. To demonstrate integrating the workflow into designing functional reticular materials, we combine the library with a genetic algorithm to identify candidate metal-organic polyhedra (MOPs) carriers for the antibiotic ciprofloxacin, with the highest-ranked candidates predicted to have low toxicity and stable host-guest interactions according to tight-binding density functional theory calculations. The concepts and relationships between the molecular fragments, CBUs, templates, and MOPs are captured and connected through a knowledge graph and ontology integrated in The World Avatar.