Markush -function

Reactive, unstable compounds, as well as covalent binders, can be removed from screening collections by substructure searches [21, 22]. At Roche, a global team of experienced medicinal chemists has defined more than 100 functionalities which are reviewed at regular intervals. This list has been augmented by unwanted features (e.g., polyacids, alkyl aldehydes, polyhalogenated phenols, etc.) which are chemically unattractive starting points for a hit-to-lead optimization, because they often result in non-optimizable SAR patterns. These chemotypes have been coded into Markush-type substructures for automated detection and removal of unwanted compounds. However, we need to stress that these filters are fully customizable, and removed chemotypes can be restored if required. 

Markush structures follow a similar approach. They were named after Eugene Markush, who used these structures to include them in a U.S. patent in the 1920s (U.S. Patent 1506316). In general, a Markush structure is a chemical structure with multiple functionally equivalent chemical entities (residues) allowed in one or more parts of the compound. Residues are structure fragments of not fully defined structures. The knowledge of these structure fragments is important to the analyst in evaluating a reaction path or a metabolic pathway. 

Markush Structure is a chemical structure with multiple functionally equivalent chemical entities (i.e., residues) allowed in one or more parts of the compound. Markush structures are a specific instance of generic structures. 

A wide variety of substructure search parameters are available. Among the more noted parameters is the ability to allow for variable substituents. This function is similar to the R group used to represent radical groups in Markush-type structures. Taking the function a step further, CSIS allows for variable positions to be designated on the main structure of the query. Although more flexible, this function is similar to the use of the slashed ring. Both of these functions can be combined, thus substantially... 

Since in the decision tree related structures are located in non-distant parts of the tree, the system is well suited to the simultaneous retrieval of a set of similar structures, therefore the HTSS system is able to retrieve very complex Markush queries with good response times. A biographical multiwindow technique has been implemented in the user interface of the HTSS system to enable the easy entry of Markush queries. Functional groups can be defined by the user as special atom types. 

CD/ChemSketch is a freeware for drawing chemical structures including organics, organometallics, polymers, and Markush stmctures [31]. It has options for structure cleaning, viewing and naming, inch conversion, stereo descriptors etc. For freeware, no technical support is provided and the functionalities are less compared to the commercial version which has structure search capabilities (Fig. 1.5). 

Schmuff has published a comparison of MARPAT and Markush DARC software. To generalize, at this stage both commercially available systems have similar capabilities in terms of retrieval and overall functionality. Both systems have the ability to represent in their databases and queries generic nodes typical of Markush structures in patents. Both systems have translation capabilities between generic node.s and specific nodes in database records and queries, and both systems have the ability to highlight elements in the database record that caused the retrieval. The similarities no doubt reflects the Sheffield connection, which both Questel and STN supported, but also the demands the patent searching community, which the developers of both systems consulted with extensively. 

---