Guiding Similarity Search in Chemical Fragment Spaces with Weighted Fingerprints.

The introduction of chemical fragment spaces as a way to model large chemical spaces led to readily available compound libraries several orders of magnitude larger than seen before. The possibility of efficient similarity search based on molecular fingerprint comparison in such chemical fragment spaces was introduced by the SpaceLight algorithm for the first time. In this work, we introduce weighted SpaceLight, an enhancement that allows the algorithm to focus the search on important areas of a query molecule, increasing the local similarity while increasing variability in other areas, ultimately providing more structural control over the results. Due to the size of chemical fragment spaces, such customization methodologies become crucial to avoid millions of hits which have to be postfiltered. We demonstrate how weighted SpaceLight produces more molecules that preserve selected substructures during similarity search and how it can be adapted for different search scenarios. Combining global fingerprint similarity with a focus on specific substructures bridges the gap between existing search methods like SpaceLight and SpaceMACS and offers a new level of control for chemical space exploration in drug discovery.