Background Molecular fingerprints are essential cheminformatics tools for virtual
screening and mapping chemical space. Among the different types of fingerprints, substructure
fingerprints perform best for small molecules such as drugs, while atom-pair fingerprints
are preferable for large molecules such as peptides. However, no available fingerprint
achieves good performance on both classes of molecules. Results Here we set out to
design a new fingerprint suitable for both small and large molecules by combining
substructure and atom-pair concepts. Our quest resulted in a new fingerprint called
MinHashed atom-pair fingerprint up to a diameter of four bonds (MAP4). In this fingerprint
the circular substructures with radii ofr = 1 andr = 2 bonds around each atom in an
atom-pair are written as two pairs of SMILES, each pair being combined with the topological
distance separating the two central atoms. These so-called atom-pair molecular shingles
are hashed, and the resulting set of hashes is MinHashed to form the MAP4 fingerprint.
MAP4 significantly outperforms all other fingerprints on an extended benchmark that
combines the Riniker and Landrum small molecule benchmark with a peptide benchmark
recovering BLAST analogs from either scrambled or point mutation analogs. MAP4 furthermore
produces well-organized chemical space tree-maps (TMAPs) for databases as diverse
as DrugBank, ChEMBL, SwissProt and the Human Metabolome Database (HMBD), and differentiates
between all metabolites in HMBD, over 70% of which are indistinguishable from their
nearest neighbor using substructure fingerprints. Conclusion MAP4 is a new molecular
fingerprint suitable for drugs, biomolecules, and the metabolome and can be adopted
as a universal fingerprint to describe and search chemical space. The source code
is available atand interactive MAP4 similarity search tools and TMAPs for various
databases are accessible atand.
