Bringing Markush Functionality to Medicinal Chemists – Introducing Markush Editor

Markush structures are widely used in combinatorial chemistry, and patents to define large collections of chemical compounds. However, handling complex Markush structures with existing general structure editors, including MarvinSketch from ChemAxon, is extremely challenging. Wikipedia has the following to say about Markush claims:

Mainly used in chemistry, but not only, a Markush claim or structure is a claim with multiple “functionally equivalent” chemical entities allowed in one or more parts of the compound. According to “Patent Law for the Nonlawyer” (Burton A. Amernick; 2nd edition, 1991),

“In claims that recite… components of compositions, it is sometimes important to claim, as alternatives, a group of constituents that are considered equivalent for the purposes of the invention…. It has been permissible to claim such an artificial group, referred to as a ‘Markush Group,’ ever since the inventor in the first case… won the right to do so.”

If a compound being patented includes several Markush groups, the number of possible compounds it covers could be vast. No patent databases generate all possible permutations and index them separately. Patent searchers have the problem, when searching for specific chemicals in patents, of trying to find all patents with Markush structures that would include their chemicals, even though these patents’ indexing would not include the suitable specific compounds. Databases enabling such searching of chemical substructures are indispensable.

Markush structures can be very complex with thousands of R-group fragments in multiple nested levels, and they usually contain additional variability features like bond variations, position variations, frequency variations, homology groups, among other attributes.

Recently, ChemAxon released a new Markush Editor that allows chemists to begin working with these complex chemical systems. ChemAxon’s Markush representation covers the full range of Markush features, and provides the most advanced Markush technology in the market to help users create, enumerate and search Markush structures. Since version 6.3, ChemAxon has added the new Markush Editor to their family of products.

Markush Editor is the first commercially available structure editor primary designed for creating and editing complex Markush structures. The main concept and the user interface design came from the previously existing Markush Viewer, but from a technology perspective, Markush Viewer was outdated and not a good starting point to add the extensive editing capabilities. So ChemAxon’s team started revising the topic with completely fresh eyes, a strong image of where they want to go, and armed with a list of customer’s use cases.

Markush Editor is a simple and intuitive tool for editing complex Markush structures. Markush Editor represents the hierarchical nature of a Markush structure in a graphical form. It contains many advanced visualization features to help the users  better understand the chemical space covered by Markush structures. For instance, the nesting view can visualize the reference chain of selected R-group fragments.

The interactive preview generates on-the-fly enumeration constricted to the selected fragments, and gives representative examples of how these fragments are built in the enumerated compounds. Users can edit complete R-group definitions or selected individual fragments. The image below provides an example of the enumeration process:

A Markush Structure with Several R-Groups and the Enumerated Compounds

A Markush Structure with Several R-Groups and the Enumerated Compounds

The sketch component is customized according to the special needs of Markush structures. For better usability, all unnecessary features are removed and some frequently used Markush features, like adding R-group attachment points and drawing position variation bonds, are added to the toolbar. To guarantee the consistency and high quality of the created Markush structures, Markush Editor contains a built-in two-level structure checking functionality. The first level checks the fragments and R-group definitions in the sketch window, while the second level validates the consistency of the full Markush structure. This way the user can easily find and fix any drawing errors or inconsistent references.

Markush Editor also helps in navigation inside large Markush structures. From the R-group combo box, any R-group number can easily be selected, and the tree view and fragment view automatically navigate to the selected R-group. If the selected R-group has multiple occurrences, the application highlights the other appearances of the R-group in the tree view. If an error message, or warning is selected from the structure checker view, the application also navigates immediately to the problematic structural fragments. The image below shows an example of an error within a sample structure:

Red Boxes Show the User where there are Errors in their Structure

Red Boxes Show the User where there are Errors in their Structure

Standard editor functions are also implemented such as undo, redo, opening and saving in various chemical formats, user interface customization, and support for multi-screen display. Furthermore, Markush Editor can simultaneously handle multiple Markush structures on a tabular interface.

In the latest version of Markush Editor, a new end extremely powerful function, the Markush Composer wizard is introduced. With the Markush Composer wizard IP professionals, or chemists can generate Markush structures which are based on a collection of compounds. The algorithm is capable to processing hundreds of compounds in a few seconds, and generate a Markush structure, which completely covers the starting compounds, and surrounding chemical space. The composition process can be controlled by some simple wizard settings. The user can also easily decorate or modify the generated “raw” Markush structure in the editor, for example they can use the structure as a stable starting point for formulating patent claims. Obviously, this function can be used not only in the IP area, but it is useful for creating combinatorial Markush structures as well.

The initial release of the Markush Editor is only the first stage of a long-term development. There are many usability improvements in the pipeline, for example new Markush checker and standardization features and, handling of R-group aliases. The Markush Editor will also be integrated with the new computer assisted chemical information extraction tool, ChemCurator, which will be launched later this summer. A link to a poster covering its functionality can be found by clicking below:

ChemAxon-Patent-Curation

ChemAxon is also planning to make Markush editing available in Instant JChem by the end of this year. There will also be upcoming improvements to the composer algorithm. Currently, it supports only R-groups, but other Markush functions, like atom lists, bond lists, position variation bonds are coming soon.

Markush Editor is available as a standalone desktop application. To run this application users will need to download, and run the Markush Editor installer. Without a valid Markush Editor license the Editor can be used in viewer only mode. In this mode all the advanced visualization features are available but you can’t create, edit or save your structures. Markush Editor can also be integrated in to your own application as a component from the JChem API.

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