In similarity-driven virtual screening, molecular fingerprints are widely used to assess the similarity of all compounds contained in a chemical library to a query compound of interest. This similarity analysis is traditionally done for each member of the library individually. When encoding chemical spaces that surpass billions of compounds in size, it becomes impractical to enumerate all their products, let alone assess their similarity, deeming this approach impossible without investing a substantial amount of resources. In this work, we present a novel search algorithm named SpaceLight for topological fingerprint similarity searching in large, practically non-enumerable combinatorial fragment spaces. In contrast to existing methods, SpaceLight is able to utilize the combinatorial character of these chemical spaces for efficiency while maintaining a high correlation of the description of molecular similarity to well-known molecular fingerprints like ECFP. The resulting software is able to search prominent spaces like EnamineREAL with more than 10 billion compounds in seconds on a standard desktop computer.