Chemical Space Docking

Extracting Relevant Chemistry from Molecular Macrocosm

Chemical Space Docking grants you access to ultra-vast Chemical Spaces encompassing billions or even more molecules.
Instead of relying on resource-intensive brute force docking of compounds typically employed in conventional virtual screening, Chemical Space Docking prioritizes the selection of the most promising candidates that effectively extend into the binding site.
Results retrieved are synthetically accessible, and in the case of our partners' Chemical Spaces, also commercially available.

The interactive workflow enables users to engage with the results at every stage, effectively guiding the project towards success.

The Concept of Chemical Space Docking

The concept of Chemical Space Docking is an efficient, structure-based exploration of ultra-vast compound collection.
Rather than employing brute-force docking of over billions of compounds, a method that could take months to years to finish, Chemical Space Docking focuses only on promising and relevant chemistry to save computation time and resources. Poorly performing drug candidates are rejected at the beginning of the workflow, putting the focus on only the interesting options.

Starting from the smallest feature that create a drug candidate, namely the building blocks, full-fledged compounds are combinatorially assembled within the binding site. Using defined chemical reaction rules, the resulting compounds are synthetically accessible and are available for purchase through our affiliated compound vendors.

Getting Started: Anchoring of Synthons

The workflow starts with the docking of the building blocks that are used in the creation of the selected Chemical Space.
In this step, you have the opportunity to apply pharmacophore constraints at your defined binding site. This will guide the placement of synthons (the initial starting fragments for compounds) and identify those capable of forming desired interactions with the target.

Once the synthons have been docked, you can examine the produced poses with the visual support provided by SeeSAR. Each synthon is equipped with a marker indicating its extension direction, referred to as a 'linker atom', thereby simplifying the evaluation process.

The chosen candidates then move forward to the next phase of the workflow: the extension stage.

Extension of Synthons: Evolving into Drug Candidates

After the anchoring phase, selected synthons expand into drug-like compounds during the extension stage. Here, the initial fragments are combined with other building blocks following chemical reaction rules of the Chemical Space. Only compounds that can be synthesized are created and assessed for their interactions at the binding site.
The setup within SeeSAR swiftly processes the docking of the extended compounds with precision to ensure they mirror the binding mode of the synthon starting point. This approach is several times faster than conventional docking methods and guarantees that the evolved compounds match the orientation of your starting fragment.

Again, you as a user can guide the process with pharmacophore constraints to introduce additional interaction patterns into the results.

Once the calculations have finished, you are presented with results of two kinds: Compounds without a linker and those without a linker. Compounds without a linker are final molecules that can be ordered or synthesized. Compounds still containing a linker require an additional extension run that will lead to final molecules.

Advantages of Chemical Space Docking

Save time — A lot of it!

Docking of billions of compounds can take up months to years to complete on standard hardware. Chemical Space Docking does the same in days — only a fraction of time!

Interactive workflow

You know your target best. Use your knowledge to guide your screening by applying pharmacophore constraints. Furthermore, SeeSAR helps you to cherry-pick the best candidates for follow-up by providing you with visual support to understand your target-ligand complex.

Several Chemical Spaces available

Collaborations with our compound vendor partners have led to a variety of commercial Chemical Spaces. Each one of them comes with unique building blocks and in-house reactions that lead to unique compounds.

Sophisticated user interface

SeeSAR was designed to be fast, visual AND easy. Every stage of the Chemical Space Docking workflow is easy to understand and to operate. With this, computationally-unexperienced medicinal chemists and even drug discovery beginners can delve into ultra-vast compound collections for novel IP and promising results.

Runs on standard hardware

No need for extensive computational resources. SeeSAR and Chemical Space Docking are easy to set up, making them accessible even to smaller companies and research groups.

Retrieves molecular novelty

Chemical Space Docking was shown to mine novel and potent chemotypes from Chemical Spaces. It can retrieve diverse chemistry complementing different subpockets of the target, fueling your pipeline with a variety of scaffolds.

Advantages of Chemical Space Docking

Random Docking Wastes Time — Be Smarter

It has been demonstrated that sampling random molecules leads to abysmal docking scores for over 95% of the ligands in the majority of cases.
Essentially, this implies that in conventional virtual high-throughput screening a significant portion of computations is allocated to fundamentally unsuitable candidates.

In comparison to brute-force docking methods, Chemical Space Docking significantly accelerates the process, efficiently enriching a diverse set of high-scoring compounds in a fraction of the time.
Boldly said, you discover more and superior compounds at a faster pace.

Harvest Your Full Potential

You can also create your own, bespoke Chemical Space using in-house building blocks and chemical reactions to define hunting grounds only you have access to. It does not require much to reach billions or even more due to the combinatorial nature of the method.
The beauty of the approach will provide you with compounds that you can easily synthesize in one or two steps while browsing through ultra-vast compound numbers.
This can enormously accelerate your in-house projects while maximizing the scope of your intellectual property.

We also offer the generation of your own Chemical Space as a service.

Be Among the First to Test Chemical Space Docking

If you are just as excited as we are about delving into more than billions of compounds in structure-based approach and cannot wait for the official release, then this is your opportunity to preview Chemical Space Docking before anyone else can.
As a beta tester, you will be at the forefront of Chemical Space exploration before it becomes widely available. We value any feedback and will consider it during development to shape the final product into a catalyst for success.

Apply as a tester to receive access to SeeSAR and its Chemical Space Docking mode. With the sophisticated user interface, everybody can easily operate the workflow and access billions of compounds at any target of interest.

Does Chemical Space Docking spark your curiosity?

Success Stories of Chemical Space Docking

In collaboration with Genentech, the CSD approach was applied to identify inhibitors of ROCK1 kinase from almost one billion commercially available synthesis-on-demand compounds. From 69 purchased compounds, 27 (39%) had Ki values <10 µM. Two leads were crystallized with the ROCK1 protein, and the structures showed excellent agreement with the docked poses.
Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors.
Beroza, P.; Crawford, J.J.; Ganichkin, O.; Gendelev, L.; Harris, S.F.; Klein, R.; Miu, A.; Steinbacher, S.; Klingler, F.; Lemmen, C.
Nature Communications 2022, 13 (1).

Starting from four small molecule fragment complexes of Protein Kinase A (PKA), CSD was performed in collaboration with Crystals First to screen for novel inhibitor chemotypes. Out of the 93 synthesized molecules, 40 (43%) were active. The best follow up of the fragments displayed a 13,500-fold gain in affinity and six X-ray crystal structures were obtained. The whole process took only nine weeks.
Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.
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.
Journal of Medicinal Chemistry 2022, 65 (23), 15663-15678.