Markush Search and Enumeration

ChemAxon’s solution for handling Markush structures

Markush structures, or generic structures, are widely used in combinatorial library and chemical patents to define large chemical spaces and to protect intellectual property. ChemAxon provides powerful Markush structure analysis tools, including importing and rapid structure search in patent Markush structure space. As a result of a collaboration with Thomson Reuters, ChemAxon’s technology is 100% compatible with all patent features of the Thomson Reuters’ standards, including the Markush database (MMS), patent document (DWPI) and exemplified structures (DCR) content. All Markush analysis features are available as an add-on for ChemAxon’s JChem technology (JChem Base, JChem Cartridge and Instant JChem).

Markush structure sketching

Markush structures can be drawn using MarvinSketch. It supports Markush structure variations, such as atom list, bond list, position variation bond, link nodes and repetition units. It also supports complex Markush features, such as multiply-connected R-groups, heavily nested R-groups, and homology groups. Numbered attachment points can be added to multiply-connected R-groups to accurately align to the core or their parent R-groups.

Markush structure generation

Besides drawing it manually, a Markush structure can also be generated automatically from a molecule library using R-group decomposition. Starting with the definition of the common scaffold pattern, this process identifies all possible R-group substituents that occur in the library. Using these substituents an R-table can be created and saved, or the scaffold can be saved in a Markush structure along with the R-group definitions. R-group decomposition is available as a command line tool within Fragmenter as well as in Instant JChem and as a KNIME node.

Markush Viewer

For a complex Markush structure with many R-groups, visualization can be challenging. The Markush Viewer can import and display a Markush structure graphically. The Markush core and all R-groups are listed in a hierarchical format. Users are able to click and review different substituents of each R-group.

ChemAxon’s Markush Search

Searching in Markush spaces

Markush Search is a powerful tool for structure search in a large chemical space defined by a generic Markush structure, without actually enumerating the explicit compounds. This approach enables the exploration of extremely large Markush spaces, which would be unthinkable by traditional search techiques. In case of multiple substructure queries against a library of Markush structures, an “Overlap Analysis” can be applied, returning the hits for each query structure spearately. ChemAxon’s Markush technology now allows users to submit Markush structures of limited complexity as a query. Query Markush structures can contain the same Markush features that can be present in general Markush structures, which makes the comparison of simple Markush spaces possible.

Rich visualization features

Hit coloring and automatic structure alignment make the visualization of the search results easier. The features for better visualization include 2D-cleaning for the hit structures. Users may also choose to reduce visualization on the Markush core only; alternatively, non-relevant R-groups can be filtered out to display only essential information or all R-groups can be shown.

Markush reduction

For an even “cleaner” display, Markush Reduction can be applied. This feature can add the R-groups matching the query to the original core, so the expanded core contains the substructure query. The R-groups in the expanded core are kept in display while the others are removed. The part of the extended core matching the query is also highlighted.

ChemAxon Markush Enumeration

Markush Enumeration is a powerful tool for Markush structure analysis and is fully implemented in JChem. By interactively guiding the enumeration of the Markush Structure users can quickly understand the relevance of Markush to their needs. Current enumeration types include; full, partial, and random enumeration; library size calculation; homology enumeration.

Filter enumerated structures

To reduce the often large library sizes after Markush enumeration, the resultant structures can be filtered by predicted properties, using ChemAxon’s many structure based calculations (either singly or combined) to identify structures with suitable chemical properties.

Markush code generation

In the combinatorial chemical application of the Markush technology the unique identification of the enumerated structures can be essential. Therefore, a special ID number can be generated for the library members. Every structure gets its own unique tag (molecule property), which can be saved in the structure file (in .mrv and .sdf formats) named as ‘Markush Code’. This ID is available in the plugin result window.  It can provide structural information, such as R-group number; link node on an atom; bond between atoms; position variation bond between atoms, etc. It may also contain customized identifier and names for the Markush structure.

Thomson Reuters patent database

Thomson Reuters and ChemAxon have formed a strategic partnership enabling users for the first time to host, search and analyze Thomson Reuters full IP Data Feeds, including Markush structures. The arrival of this search and analysis solution will speed drug discovery and allow life science researchers and IP experts to easily integrate critical content into their existing systems and workflow. Thomson Reuters Markush DARC (.vmn) files contain Markush structures extracted from patents. Each VMN file contains one Markush structure. These VMN files can be imported to the JChem technology  as Markush structures.

ChemAxon offers assistance with the loading of raw files provided by Thomson Reuters into a cross-linked relational database structure. This database includes textual, Markush and specific (e.g. exemplified) chemical structure data. Instant JChem is an ideal tool to search such a complex database scheme.

Markush structures in a workflow

Workflow management solutions play a more and more important role in everyday research processes. ChemAxon’s Markush analysis plug-in is implemented in KNIME and in Pipeline Pilot, two commonly used workfow management toolkits. These implementations includes Markush Search, Markush Enumeration, and Markush structure generation which makes this technology easily accessible and integratable into best practice routines.

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