Chemical Space Docking

Chemical Space Docking at BioSolveIT

Chemical Space Docking — Combinatorial Binding Mode Exploration

Chemical Space docking is our novel approach in the toolbox of virtual screening: We are now able to handle massive numbers of molecules occurring in combinatorial Chemical Spaces. In analogy to known virtual screening methods, Chemical Space Docking aims to predict actives based on their binding mode after a docking procedure with subsequent scoring of the complexes. Yet the source of the docked molecules is no longer an enumerated library but a combinatorial built-up "Space" of zillions of molecules.
In the initial step, all building blocks are docked. Since these act as an "anchor" before growing to full molecules, this represents only a small fraction of all molecular possibilities in the start. Subsequently, after assessment of those, lead-like compounds are built up: Controlled by sensible, "experience"-steered chemical reactions the anchor is further grown with further building blocks.
Thus, without docking every single, full entry of millions or billions of compounds, the entire Chemical Space is investigated for potential hit compounds, and every member has an a priori chance to emerge as a hit — yet only a fraction of the computational resources is required. Truly "Green Computational Chemistry".
This approach is one of our contract research services. In the following description every step of the Chemical Space docking will be elaborated.

Initial Step - Building Block Docking

Instead of docking the total of 10¹⁵ or more of compounds in a Chemical Space, only a small fraction — the building blocks used to create the space — are used. This step is important, as conventional docking of every single compound would require thousands of years of computation. What follows is an energetic assessment of the binding modes. Here, a known method from fragment-based drug discovery, the growing of small molecules, plays a key role. Binding modes of interesting candidates are investigated for extension possibilities at molecular functionalities (presented as colored building blocks in the figure). As per definition, chemical building blocks are the fundamental elements to construct a larger molecule with desired properties. Those molecules with potential to be evolved into good binders enter the next step.

Combinatorial Compound Generation

Using a defined set of chemistry rules, a Chemical Space is built up with the candidates. With knowledge on what functional groups or moieties of a molecule can be combined with those of other building blocks, offsprings of predicted binders are created and again docked into the target. This method allows the exploration of the whole Chemical Space with a minuscule of the computational efforts required otherwise. Bad fragments that would disqualify a larger compound for further consideration are ruled out during every step allowing to focus only on what is likely to succeed.
The growing step can be repeated as many times as needed, so each run expands the Chemical Space in a combinatorial fashion. Imagine: One run with 1,000 building blocks with a group A and 1,000 building blocks with a group B explores the Chemical Space of 10⁶ compounds. Elongation of those molecules with another set of 1,000 building blocks with a group C results in an expansion to the size of already 10⁹. We can certainly go beyond.

Accessible Results

After the redocking of generated compounds, the final binding mode assessment & filtering, our Chemical Space Docking delivers a set of molecules that are likely to bind to the target of interest. Since chemical rules have been applied to create the Chemical Space (e.g. robust chemical reactions or in-house knowledge), hit candidates have a high likelihood of synthetic accessibility. Several pharmaceutical companies already utilize the concept of combinatorial reaction chemistry to create their own, proprietary Chemical Spaces. Renown chemical compound makers have inhaled the power and possibilities behind this approach and responded with their own Chemical Spaces: Users can search for commercially available, "make-on-demand" compounds. The application of robust in-house chemical reactions is reflected in a high synthetic success rate and delivery rates of few weeks.

If you got interested in Chemical Space docking for your drug discovery projects as a service, contact us and we will provide you with further information.

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