SMIRKS transformation

It is possible to use SMIRKS transformations to modify SMILES to conform to a standard valence model. For example, if a SMILES for nitromethane is entered in the charge separated form C[N+](=0)[0-], it can be transformed to the other form CN(=0)=0. Chapter 9 discusses transformations and gives examples that will help resolve issues with structures that can be represented equally well using two distinct valence forms. 

One way to resolve this issue in a database is to require one particular form for the nitro group. Putting the burden on the chemist who inputs the structures is possible, but when hundreds or thousands of structures need to be imported, say from a vendor or other library, examining and correcting hundreds of individual structures is not feasible. Using a SMIRKS transformation can easily solve this problem. 

The std smirks table would contain the standard transformations. Chapter 9 shows a sample table of standard SMIRKS transformations. This table could be expanded at any time to include more standardizations as they become necessary without having to modify the trigger function to deal with these additions. 

Daylight has extended SMILES rules to accommodate general descriptions of molecular patterns and chemical reactions (13). These SMILES extensions are called SMARTS and SMIRKS. SMARTS is a language for describing molecular patterns while SMIRKS defines rules for chemical reaction transformations. 

Like Molfile, SMILES is a member of a whole family of related formats. The other members are SMARTS (SMiles ARbitrary Target Specification) for description of structural patterns and SMIRKS for description of chemical transformations. Of these, SMILES is by far the most commonly used. 

The binding calculator computes the feasibility of a particular vMol binding to a vEnz, based on quantitative structure-activity relationships (or decision tree) derived from properties of known substrates for each enzyme. Transformations are stored as a list of SMIRKS (SMILES Reaction Specification)... 

In Chapter 9, chemical reactions and transformations are discussed. Using SMIRKS to represent chemical transformations, reaction specifications can be stored in the database. Structures can be transformed and combined (reacted) to produce new structures. 

The use of Simplified Molecular Input Line Entry System (SMILES) as a string representation of chemical structure makes possible much of what has been discussed in earlier chapters of this book. A chemical reaction could be represented as a collection of SMILES, some identified as reactants and some as products. It is possible to define a table to do this, or perhaps use some arrays of character data types, but a syntax extension of standard SMILES allows reaction to be expressed easily. SMIRKS is an extension of SMILES and SMiles ARbitrary Target Specification (SMARTS). It is used to represent chemical transformations. SMIRKS can also be used in a transformation function to combine SMILES reactants to produce SMILES products. 

This chapter describes some of the aspects of SMIRKS and shows how it can be integrated into a relational database using new structural query language (SQL) functions. It discusses ways in which chemical transformations and reactions can be used to improve the robustness and usefulness of a chemical relational database. 

The word reaction is typically used to represent a specific reaction as well as a general transformation. In this chapter, the word reaction is used to mean a specific reaction represented using reaction SMILES. The word transformation is used to indicate a change in a set of reactants to products. SMIRKS is the language used to specify precisely how this transformation is to be carried out. 

In order to carry out a transformation, it is necessary to know precisely which bonds are to be broken and which are to be made. While this information is implicit in the SMIRKS above and can be understood by any chemist, a more specific set of instructions is necessary in order to make the transformation possible using a computer. Numbering the atoms of the reactants and the corresponding atoms in the products accomplishes this. This produces an atom mapping. Many sketching programs can do this automatically or with some additional input from the user. Using the example shown previously, an atom-mapped SMIRKS would... 

Before considering how SMIRKS can be used to carry out transformations with multiple reactants, first consider simpler unimolecular transformations. These are discussed separately because of the important use of unimolecular transformations to enforce the consistent use of SMILES throughout the database. This improves the integrity of the data in a chemical sense, rather than a relational database sense as discussed previously. The root of the issue is this There are multiple ways to represent the same molecular structure due to the limitations of valence bond theory. In valence bond theory, upon which SMILES is based, atoms have formal charges, most often zero. The bonds between atoms are shared pairs of electrons and may consist of multiple shared pairs giving rise to double, triple, or possibly even higher-order bonds between atoms. This simple theory, while quite powerful and applicable to a majority of chemical structures, leads to certain ambiguities. 

Suppose it is decided that the valence 5, noncharge-separated representation of the nitro group is to be used throughout the database. The SMIRKS [0 2]=[N+ 1][0- 3] [0 2]=[N+0 1]=[0+0 3], when applied to any charge-separated nitro group will transform it into the proper form. This is accomplished by creating another new SQL function, xform(smiles, smarts). As with the cansmiles and matches functions, this is an extension to standard SQL. Some form of this transformation function is... 

The standardize function checks whether any smirks in the std smirks table, when used in the xform function, results in a modification of the input SMILES stored in NEW.smiles. If the xform function does return a transformed SMILES, then that transformed value is used in place of the value the user attempted to insert. Finally, the trigger is created using the standardized function to possibly modify any SMILE before inserting or updating a table. 

SMIRKS allows one to express a multicomponent transformation as well as unimolecular transformation as discussed previously. The following SMIRKS shows how to transform a combination of an acid chloride and an amine into an amide. 

Because SMIRKS is a combination of SMILES and SMARTS and because there is no canonical representation of SMARTS, there is no canonical representation of SMIRKS. SMARTS can be considered as a set of instructions on how to match substructures of SMILES. SMIRKS can similarly be considered as a set of instructions on how to identify reactive atoms and combine or alter them in order to carry out a specific transformation of a set of SMILES. 

Encoding the transformations made use of technology provided by Daylight Chemical Information Systems, Inc. (www.daylight.com). While most medicinal chemists are commonly aware of the SMILES (Simplified Molecular Input line Entry System) code created by Daylight, less familiar is their SMIRKS system for encoding transformations of one SMARTS pattern into another SMARTS pattern. Key to the... 

Figure 11.2 SMIRKS coding system (www. daylight.com) illustrated for the Hydroxy-to-Methoxy transformation. A mapped atom, designated with the number 1, is defined to be either an aliphatic, C, or aromatic, c, carbon-based group. On this mapped atom 1 is attached an OH group. The transformation is denoted with >> in the center of the SMIRKS code. The right-hand side ofthe equation shows that the OH is changed to —O—, with the addition of a new aliphatic atom, C. Hydrogen...

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