# Guiding Similarity Search in Chemical Fragment Spaces with Weighted Fingerprints

## TL;DR

This paper introduces a new method to improve chemical similarity searches by focusing on important parts of molecules, making the search more efficient and precise for drug discovery.

## Contribution

The paper introduces weighted SpaceLight, a method that enhances chemical similarity search by allowing structural control through weighted fingerprints.

## Key findings

- Weighted SpaceLight increases local similarity while allowing variability in other areas of the molecule.
- The method produces more molecules that preserve selected substructures during similarity search.
- It bridges the gap between existing search methods like SpaceLight and SpaceMACS.

## Abstract

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.