Markush feature

Table 9.4 Example Molfile Showing Markush Features, Atom, and Fragment Data... 

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. 

Figure 9.8. Structure representation with additional information, including atom (partial charge) and fragment (percent composition) data and Markush structure features.

Figure 9.8 shows a structure that contains atom (partial charge) and fragment (component percent) data of various types, as well as Markush structure features (Ri). Table 9.4 shows the corresponding structure-data file (MDL sdfile). Each Rgroup member appears in its own "submolfile" in this file representa-... 

Logic in Query Features. Using AND, OR, and NOT as modifiers on the application of query features. For example, one could run a search to select structures that contain "halogen and not primary or secondary amine, or not halogen and any amine." The logic can be a part of the query substructure, as with Markush queries, or it can be part of the SELECT statement. 

Generic or Markush structures are a form of structural representation that can be used to encompass many individual molecules having common structural features. Figure 6.5 shows a simple example. They are particularly associated with chemical patents,but may also be used (often with a table of values for the R-groups) to represent sets of related molecules involved in structure - activity relationship studies, or large combinatorial libraries. The RGfile variant of the Molfile format can represent restricted forms of Markush structure, as can Sybyl line notation,and a variety of vendors have implemented ad hoc extensions (which have some Markush capabilities) to SMILES. 

Computer standardisation of structures requires that the structure be completely defined, without variable sites a change in a variable may completely alter the way that the machine interprets the structure as a whole. Working through all of the specifics implied by a Markush, and subjecting each in turn to structural feature... 

Additional structure-based databases like the CAS Markush file are being built which require new features, including the ability to more closely couple text and structure searching. 

A powerful feature of MDARC is the system of 22 superatoms (Table 3), most of which are generic node types commonly found and referred to in Markush structures in patents. The acyclic superatoms have attributes for low, middle, or high chain length, and straight or branched topology. The cyclic superatoms have attributes for ring system fusion and saturation. For example, a Markush may specify a particular node as... 

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