Markush-type substructures

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. 

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... 

Today, fragment coding is still quite important in patent databases (sec Chapter 5, Section 5.11, e.g., Dei went) where Markush structures are also stored. There, the fragments can be applied to substructure or othei types of searches where the fragments arc defined, c.g., on the basis of chemical properties. 

On this basis, the structure we have used for our example can be analyzed in the manner described to produce a series of three short codes, which describe not only this molecule, but also any nongeminal combination of the two substituents around the ring (see Figure 5). This is a really a similarity search in chemical structures, a capability which is complementary to a substructure search, and has some relevance for certain types of Markush representation- A brief inspection of the "chemical environment" of any randomly chosen region of ca. 30 pages of the Handbook will demonstrate the strengths and limitations of this approach. 

A structure search of chemical substances can be performed in the chemical structure databases. The structure query can be input using a graphical structure editor. The following search methods are possible, depending on the type of structure database. The structure search capabilities depend on the software system. Here, the focus is on the implementation of STN International exact structure search, family search, substructure search, similarity search, generic (Markush) search, and reaction search. 

Markush searches are generic substructure searches. It should be clear that both structure queries and structure files may contain specific and/or generic Structures. In a Markush search generic chemical structures are searched against a database which contains specific or generic structures. The first type of database is a registry file, e.g., the CAS REGISTRY, and the second type is a Markush file, e.g., MaRPAT (see Structure Representation). 

In the case of the second problem, however, it is both possible and desirable to give a definition of the search tool, and that is the purpose of this paper. The LN is a flexible and useful tool, but contains the seeds of much difficulty if the concept is applied incautiously. It is not a type of substructure searching, nor is it a Markush search. To repeat the above objective once more, the intention behind the LN is to retrieve those sorts of structures which one might have found within a few pages of the given structure, had the user been looking in an Omnibus Edition of the Beilstein Handbook. 

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