Report:MARPAT on STN/Chemical Structure Tools/Variable Groups

Generic Structure Searching: Variable Groups

The simplest way to define a generic group of allowable substitutions in STN Express is to use one of the pre-defined “variable nodes” available in the drawing tool. Adding a variable group to a structure query in STN will restrict the substitution possibilities to only those atoms or structure fragments belonging to the designated chemical class. The following variables are available in the STN structure module:

Customizing Variable Groups: Generic Definitions

Some of the variable nodes in the list above are customizable. Along with normally defined atoms, single atom variable groups (such as M, X, A and Q) can be further narrowed with other attributes relating to charge, valency, and isotope number. The figure below shows that users may specify a charge of up to 30 (negative or positive), a specific or abnormal isotope, or a specific or abnormal valency on a particular atom or variable group.

Single atoms and variable groups may be further defined by adding charges, valency parameters, and isotope parameters via this dialog window.

Ring and chain system variable groups are also customizable. When defining any ring system (Cy), a heterocyclic ring (Hy), a carbocyclic ring (Cb), or an alkyl chain (Ak), searchers have the option to assign further generic definitions. Briefly, generic definitions are used to specify:

• Whether the system is saturated or unsaturated
• Type of alkyl chain (linear vs. branched)
• Number of heteroatoms (non-carbon atoms)
• Monocyclic vs. polycyclic ring systems
• The number of carbon atoms in the system (less than 7 vs. more than 7)

The figure below shows the dialog window which is used to set these generic definitions. Only definitions appropriate for the chosen variable group are displayed in black; options are grayed out when they do not apply. The window below shows the available definitions for an Hy variable node, and the chain-length definition is not available for that option as it represents a cyclic group.

The generic definition window allows users to narrow the scope of a variable group representing a ring or chain.

Customizing Variable Groups: Non-Hydrogen Attachments

The Non-Hydrogen Attachments feature can be used to limit the number of potential substitutions on a variable ring or chain. In other words, the searcher may limit the number of substituent groups that are allowed to bond to a variable ring or chain, and whether those bonds are ring or chain bonds. The default setting on this parameter is “any”, so if left undefined, the number of substituents allowed on a variable group will be the maximum number available. The figure below shows the dialog window that is used to define the non-hydrogen attachments.

The non-hydrogen attachments dialog window. Users can define a minimum or maximum number of ring or chain branches that may be connected to the variable group.

Customizing Variable Groups: Element Counts

STN will allow users to define the specific type and number of heteroatoms permissible within the ring system. This feature is called the “Element count.” The figure below shows the dialog window for defining element counts: users choose the desired element(s) that should be included in the ring structure, and how many of those atoms should be allowed in the ring (choices can be exact, or to define a number as a minimum or maximum number of that particular atom). The figure below shows a heterocyclic variable group that was defined to contain exactly one sulfur atom, and up to four nitrogen atoms.

The element count dialog window for a heterocyclic ring, showing that the ring may contain up to 4 N atoms, and must contain exactly 1 S atom.

A small tick box at the bottom of the “element count” dialog window allows the user to tick the option for a “Limited” search. This option means that the element count in the resulting structure hits must be equal to the corresponding element counts in the structure query. While this option is appropriate for a search in REGISTRY, where the indexed structures are exact chemical structures, a search in MARPAT is a little different because the indexed structures may also contain variable groups. Leaving the element count “limited” in MARPAT may be artificially restrictive and eliminate potential Markush structure hits which do not require or specify a certain element count in their heterocyclic ring or chain systems. For example, it is possible in MARPAT for a patent to have a matching structure, but a portion of it may be undefined as a Hy variable group. This structure would not be found by the query with a defined element count for the Hy variable unless the element count on the query structure was defined as “unlimited.” For example, if the structure shown in the figure above were given an element count, and the “limited” box was checked, the structure query would not pick up a search result structure that exactly matched the query structure, but did not have an element count applied to the Hy variable group. In most cases, this would be a very undesirable result.

In sum, the result of using an “unlimited” element count in a query is to require a specific element count for results that have specifically defined heterocyclic rings or chains, but to make an exception for structures that contain variable groups in place of defined structure fragments, and include them even if they do not match element count requirements. This feature is just another way to customize the search query to attain the proper level of precision without excluding potentially relevant generically disclosed results.