The Fragment-based approach stands as a highly effective way to find the starting points for drug discovery projects. After identifying a potential hit fragment, the next challenge is to turn it into a lead compound by efficiently growing or linking fragments. At Chemspace, we have developed fragment libraries where each fragment has a defined growth vector and a clear path to synthesizable full molecules within Enamine xREAL Space - making it easier to turn fragment hits into real lead compounds.
By utilizing the modular nature of Enamine REAL Space, Chemspace gained access to a 2.7 trillion compound chemical space at low cost and with rapid synthesis. Our tailored fragment library serves as the perfect entry point into this space - enabling efficient and scalable fragment-to-lead discovery.
Library Creation
The REAL Fragment libraries are based on the concept of scaffold sociability, which refers to a specific fragment scaffold's ability to expand in various directions through a diverse set of reactions. By selecting social scaffolds for our fragments, we aim to simplify the process of fragment growing, as REAL fragments can be easily extended into REAL compounds.To select sociable scaffolds, we analyzed the synthons from Enamine xREAL (2.7T) using an in-house workflow. First, we grouped the synthons by scaffold and then superimposed them in 2D space. For each synthon, we calculated the exit vector, which indicates the direction of growth. Based on the symmetry of the scaffold and the number of available exit vectors, we assigned a coverage score to each scaffold. This score reflects the scaffold's sociability within the Enamine xREAL Space.
Additionally, the number of available reactions, the number of unique synthons, and other parameters were annotated to be used in further fragment selection.
REAL Fragment Library
A collection of the REAL fragments created based on 1,524 selected sociable scaffolds. The final selection of fragments for the library was performed based on pharmacophore diversity and clustering to ensure the presence of diverse chemotypes.The REAL Fragment Library is a pre-plated fragment collection that efficiently covers the chemical space of all synthons inside the Enamine xREAL Space.
REAL Crystallographic Library
Since crystallographic screens have lower throughput, we specifically designed a version of the library tailored to crystallographic applications. Due to the smaller number of compounds, the fragment selection process features not only a significantly larger number of filters but also substructure-based analysis to ensure that most fragments have substructure matches in the synthon space. The final selection was also made based on pharmacophore diversity to provide comprehensive coverage of chemotypes.
Fragment-based Drug Discovery
Once promising fragments are identified, Chemspace offers a data-driven approach to fragment growing and linking within Enamine REAL and Chemspace Freedom spaces. This workflow enables rapid transition from fragment to active molecule, supported by accessible chemistry and high synthesis success rates.