Atomic valence SMILES

The generation of the correct compound structures is a critical step in which different components such as atomic valences, correct bond orders and properly defined aromaticity have to be considered carefully. In addition, the correct stereochemistry flags need to be added for a correct treatment of stereochemistry. Most of the current pharmacophore generation packages include compound builders, but users can also import them from external sources using common file formats, for example SMILES, MOL, SD or MOL2. 

When CC is used as a SMILES, it means exactly ethane, exactly [CH3] [CH3]. When CC is used as a SMARTS, it will of course match ethane, but will also match any structure having a C-C single bond, regardless of how many H atoms are also bonded to each C. This may be exactly what was intended, but SMARTS can be more exact in what is meant. For example, the SMARTS [CH][CH0] will only match structures having a C-C single bond where one C has exactly one H atom and the other C has none. When brackets are used for a C atom in SMILES, the assumptions normally made about the valence and hydrogen count of the atom are not used. The SMILES [CH][CH0] is a strange molecule indeed and is likely an error if it is encountered. 

Similar to SMILES, InChI does not store atom coordinates. In contrast to SMILES, which by default omits hydrogen atoms that are then added implicitly to match the most common valency of an atom, InChI stores hydrogen atoms but does not store bond orders. These two techniques are just different approaches to the same problem for a given molecular skeleton, the bond orders and number of hydrogen atoms... 

SMILES (Simplified Molecular Input Line Entry System) was invented by Weininger5 to facilitate the representation and manipulation of molecular structures using computers. It uses standard atomic symbols to represent atoms and the symbols - for single bond, = for double bond, and for triple bond. Hydrogen atoms can be represented explicitly but are almost always represented implicitly using normal conventions of valence bond theory. Single bonds need not be explicitly written. For example, propane is C-C-C or simply CCC. Methylamine is CN, and C N is hydrogen cyanide. Propene is C=CC. For more complex structures with branched bonds, parentheses are used. For example, CC(C)0 is isopropyl alcohol, whereas CCCO is propanol. 

If canonical SMILES are used in a table to facilitate direct lookup of molecular structure, it is necessary that only one unique name be used for any one structure. Similarly, if one is searching for structure-containing nitro groups, it is necessary that all nitro groups be represented using the same valence conventions. For these reason, it is essential to make a decision about the use of SMILES in certain cases, such as nitro groups. Sulfur and phosphorous atoms also must be considered carefully since they are commonly found with "unusual" valence. 

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. 

It would be possible to create tables using columns to store the atomic symbols and bond information found in molecular structure files, reflecting the column style format of the file itself. Instead, a SMILES representation of this valence bond information is preferred. SMILES is a compact text string containing the same information as the columns of atom symbols and bonds. It can also be used directly in the search functions described in earlier chapters. It is desirable to parse the molecular properties in molecular structure files in order to store them in data columns for possible searching... 

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