“Crystal Structure First” Approach

Fragment-Based Drug Discovery (FBDD) has proven itself as a reliable method to discover starting points that can be optimized to become clinical candidates. After the identification of potent fragments, the fragment growth stage becomes a challenge due to the cost and time needed to synthesize custom compounds. The “Crystal Structure First” Approach brings the FBDD to a new level by utilizing the chemical modularity of Enamine REAL Space. Using this approach, we at Chemspace perform the fragment evolution to the full-size molecule hits with a remarkable boost in potency and at the price of REAL compounds. [1] crystal structure first schema crystal structure first schema crystal structure first schema Utilizing the power of our fragment libraries, we can detect the fragment(s) that bind to the target, crystalize the fragment-target complexes, and use this information to perform template-based docking of Enamine REAL Space. The molecular docking is done using the state-of-the-art software ICM-Pro by MolSoft.

REAL Fragment Library, 5,000 compounds

fragment library schema This library was designed as a perfect entry point to Enamine REAL Space, as it was built by a thorough analysis of the REAL scaffolds. For the creation of this library, all synthons were grouped by their scaffolds, and each group was superimposed in 2D coordinate space. This allowed us to select the scaffolds that have exit vectors in more than 2 quadrants. We mapped scaffolds to synthons and selected those that resulted in the most chemically diverse compounds. The final set of fragments represents the whole Enamine REAL Space including the chemical diversity and variety of chemical transformation. The important aspect of the library is that all the fragments have high sociability and the possibility to be grown in different directions to form 3D diversity of the final molecules.

REAL crystallographic Fragment Library, 480 compounds

Screening the fragments using crystallography results in detection of binding modes right after the first screen but has a much lower throughput. This is why we created a library of 480 compounds based on the REAL Fragment Library for you to be able to benefit from this approach. The compounds were selected using fingerprint-based similarity to ensure their diversity, so we can provide maximum chemical space coverage with less compounds.
fragment library schema fragment library schema

REAL crystallographic Fragment Library, 480 compounds

Screening the fragments using crystallography results in detection of binding modes right after the first screen but has a much lower throughput. This is why we created a library of 480 compounds based on the REAL Fragment Library for you to be able to benefit from this approach. The compounds were selected using fingerprint-based similarity to ensure their diversity, so we can provide maximum chemical space coverage with less compounds.
Chemical space
Crystal Structure First can be applied to Enamine xREAL Space of 2.3 trillion molecules.
Project requirements
The workflow requires crystal structure(s) of the fragment(s) bound to the target. You can provide the structures from your in-house screens, or we perform a pre-selection stage to identify the initial fragments together. Additional requirements for hit selection can be discussed upon request.
Workflow description
There are two ways of entering the “Crystal Structure First” workflow:
  • Pre-selection stage. For identification of initial fragments, we provide REAL Fragment Library and REAL Crystallographic Fragment Library, but other fragment libraries can be used as well. REAL Fragment Library can be screened by TSA or SPR methods. The potential binders will be crystalized to get the binding modes of the fragments. Using crystallography to screen the REAL Crystallographic Fragment Library we can get the binders and the binding modes for them after just one screen.
  • Template-based docking stage. If you have already completed a fragment screen, we use the obtained information to set up template-based molecular docking of the Enamine Synthons to select the synthons for enumeration. The main criteria for synthon prioritization are docking score, APF score, the direction of the reaction vectors, and ligand efficiency.
After the docking stage, a focused set is enumerated using REAL Space reactions. The compounds are then docked to the target using the template-based approach. To select the hit compounds, the top-ranked molecules from the focused space are re-docked with a higher docking effort, energy minimization for each ligand-protein complex, and utilizing AI-based RTCNN scoring function. Distance analysis towards the key residues, pocket occupancy analysis, and synthon-based clustering are used to select the final molecules for testing. After the final hit selection step, you will be provided with the list of 100-500 compounds recommended for wet screening.

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References
  1. Müller, J.; Klein, R.; Tarkhanova, O.; Gryniukova, A.; Borysko, P.; Merkl, S.; Ruf, M.; Neumann, A.; Gastreich, M.; Moroz, Y. S.; Klebe, G.; Glinca, S. Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces. J. Med. Chem. 2022, 65, 23, 15663–15678. https://doi.org/10.1021/acs.jmedchem.2c00813 .