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 with 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.
Help
Starter Package Good Practice for C-S-D

Tutorial videos

FAQ

  • Download SeeSAR 14
    • Begin by downloading the latest version of SeeSAR 14. This software provides the main interface for Chemical Space Docking™ (C-S-D), where you’ll manage your compound screenings and interact with the docking tools.
  • Download HPSee 2.0
    • Next, download HPSee 2.0, a companion tool designed for high-performance docking calculations. HPSee handles the heavy lifting for docking operations, allowing you to run large-scale screenings on a dedicated machine or server.
  • Download the CSD Starter Package
    • The C-S-D Starter Pack includes essential resources, including two setup guides and the ROCK-1 Test Space—a sample chemical space for testing C-S-D.
  • Follow the HPSee Deployment Guide
    • Install HPSee 2.0 on your dedicated machine using the detailed steps in the HPSee Deployment Guide. This setup ensures HPSee is ready to handle the docking tasks as you use SeeSAR for screening.
  • Refer to the SeeSAR Beginner Guide
    • Install SeeSAR 14 on your primary workstation and follow the SeeSAR Beginner Guide to get familiar with its interface and workflows. This guide covers the basics of navigating SeeSAR, initiating docking runs, and working with the 3D visualization tools.
  • Watch the Tutorial Video
    • If you need further assistance, the SeeSAR 14 Tutorial Video provides a visual walkthrough of setting up and using C-S-D in SeeSAR, ideal for new users.

Get the Chemical Spaces

Download here

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.

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Spotlight SeeSAR 14 Read more about C-S-D (PDF)