“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]
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 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.
References
-
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
.
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.
