Markush representations

Having the desired reactant lists, the chemist can now create a virtual library by enumerating the product structures in a fully combinatorial manner. Enumeration instructions are prevalidated for all PGVL registered reactions for a user-specified reaction, PGVL Hub enables enumeration via the Markush representation of the reaction scheme. Once the products are... 

The next issue is one of originality, that is, has anyone made these compounds or this library before The patents issue is perhaps the least well documented, although it is a common issue. The number of reactions that respond well to combinatorial approaches (to yield reasonable amounts of product of > 80% purity) is limited but growing. It is reasonable to assume that if company A uses a literature reaction, then company B will have used the same reaction, possibly to make the same products. The chances of making a unique product are therefore greatly diminshed. Unfortunately, there is no fast mechanism for checking for patentability at present, although the work of Barnard and Downs on Markush representations offers a future solution[5]. 

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. 

As we mentioned earlier, the time that is available for each diversity task will likely depend on the nature of the task. Reagent selection may need to be done in a hurry, whereas compound acquisition studies may be afforded rather more time. In the former case, it is clear that the computer time required for diversity analysis/library design must not exceed that available (possibly only days if the library chemistry is already developed, longer if the chemistry is new). For many product-based reagent selection approaches, CPU time is at present a very real obstacle to what might be done. It is to be hoped that more efficient algorithms and exploitation of parallel computation techniques will help alleviate the current difficulties. More fundamentally, the development of approaches based on Markush representations may offer a solution in instances where only simple 2-D descriptors are employed. ... 

Fig. 9.8. The remaining structures for CASE with structure 15, as Markush representations.

Markush structures rcprcHL-uts compound families - widespread in patents nianual in/ontput convertible into otlicr representations high number of compounds less compact code ambiguous difficult to extract individual compounds... 

A generic substance represents more than one substance or a set of specific substances. This set of substances can be represented by a generic or Markush structure. An important use of generic structures in the literature is that they provide a compact representation of a set of specific substances. They are also commonly used to show the way the value of a particular physical or biological property varies as a particular... 

Figure 5.9 Representation of chemical libraries Markush and reaction-based approaches.

Figure 9.6. Chemical structure data for high-throughput chemistry. The generic structure representation is often referred to as a Markush structure.

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

Markush structure A type of structure representation in which very general lemis. such us alkyl or alcohol, can be used to describe the substituents in a generic structure. Used in the patent literature and adapted for combinatorial chcmi.slty publications. 

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. 

Segment 1 denotes that a specific structure has been claimed in a patent in isolation, or as one of a very small group of specific compounds. Derwent is using Segment 1 as an efficiency factor in indexing, and in presentation to the user. For example, if there are 1,000 patents on production of aniline, the user would only wish to see one graphic aniline record, along with any representations of aniline as a possibility of a Markush. 

Markush DARC represents a system from which we can progress. Derwent and INPI have built in essential information into the database that allows for future expansion of capabilities. These capabilities include generic search, translation of generic expressions to specifics and specifics to generic expressions, and sophisticated limitations in search results. Derwent believes that the Markush DARC system should be viewed as not only a product of today, but also as an embryonic representation of what the future holds. 

The iterative search algorithm is being completely rewritten for the search engine implementation to support the use of generic search queries against a file of Markush structure representations. That is, both the queries and the structures on a file may have nodes represented as variable substructures or certain generic nodes (e.g., heterocycle). 

Another example is GENSAL, which provides a means for the representation of generic queries in an experimental system for the storage and retrieval of the Markush structures that occur in chemical patents. Here, the language allows the specification of lists of alternative substituents, of variant positions of substitution on rings, and of ranges of numbers of atoms in carbon chains. Thus, these lists reflect the very wide range of types of structural description that are found in patents for chemical substances. 

Several computational methods for generating large databases of chemically reasonable structures (virtual libraries) have been developed. They employ strategies such as the mutation of text strings representing chemical structures, the expansion of Markush structural representations, or virtual combinatorial libraries derived by exhaustive enumeration of all substituent variations at specific points on a core scaffold. An example of these large virtual libraries is the ChemSpace database, containing approx 10 trillion chemical structures for use in similarity and pharmacophore searches, approx 500,000 times more than all the compounds in Chemical Abstracts. 

Meyer, E. Topological Search for Classes of Compounds in Large FUes - Even of Markush Formulas - at Reasonable Machine Cost . In Computer Representation and Manipulation of Chemical Information Wipke, W.T. HeUer, S.R. Feldmann, R.J. Hyde, E. Eds. John WUey and Sons New York, 1974 105-122. 

AUTOMATIC TRANSLATION OF GENSAL REPRESENTATIONS OF MARKUSH STRUCTURES INTO GREMAS FRAGMENT CODES AT IDC... 

Since we have the GENSAL language (see Figure 2) for description of Markush structures , and software for translation of them into machine internal representations, we are able to derive search representations automatically. Great... 

Stiegler G. Maier B. Lenz H. Automatic Translation of GENSAL Representations of Markush Structures into GREMAS Fragment Codes at IDC . In these Proceedings. 

It should be noted that the composite structure and its corresponding connection table are the permanent and stored type of representation in the Markush structure file. 

A significant problem in the universe of Markush chemical structures is the matter of extreme complexity. Markush chemical representations leave room for ambiguity, and often extremely complex Markush structures are created that become very difficult for Markush database producers to code. Additionally, the scope of these Markush claims can be excessively broad, making establishment of the prior art essentially impossible to determine for purposes of a meaningful and defensible patent examination. Sibley has commented most eloquently on this subject, as have others. " ... 

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