LESSON 6: Building Small Molecules with SMILES

1. Build a fairly complex molecule with SMILES input

   Enter the Hint Module and select Edit from the SMILESBuilder pulldown menu. In this lesson the SMILES structure for morphine will be created and a 3D molecule object for morphine will be produced. Morphine has five rings and is a structure of about average complexity that can be generated with the Hint SMILES system. Although there are numerous correct SMILES codes for morphine, the goal is the generation of the most logical sequence. Since there are five rings, there will have to be 5 ring breaks or named bonds.

   

   As the ring breaks are depicted above, the best approach would be to begin at the aromatic carbon next to ring breaks "1" and "2" and proceed clockwise around the aromatic ring, to and through the bridgehead nitrogen, and then (clockwise) following the cyclohexenyl ring to (and ending at) the furan oxygen (ring break "3"). The SMILES string for this sequence is:

   c12c3c(O)ccc1CC4N(C)CC25C4C=CC(O)C5O3

   Enter this string into the SMILES String parameter box. The SMILES Object parameter block will default to "SMILES1". And since this molecule was not drawn with specific stereochemistry, leave Asymmetric SMILES set to off. Press Execute. Now depicted on the screen is the 2D SMILES object for morphine. It should look pretty similar to the drawing above.

2. Convert SMILES Object to 3D Molecule

   Enter the Builder module and pulldown the Sketcher menu to 3D_Convert. Since we wish to perform later operations with the SMILES object, turn KeepSketch to On. (In a later step we will modify the SMILES/Sketch Object.) Make sure Sketch Object is set to "SMILES1" and enter "MORPHINE" as the New_Molecule_Name. Press Execute to begin the 3D conversion. At completion, a 3D model of morphine should be displayed on the screen. You may wish to further optimize this structure with Discover.

   Morphine molecule created with SMILES input

3. Manipulation of SMILES files

   SMILES files are ASCII files with two items per record: the first is a SMILES string, and the second is an optional name for the molecule represented. A SMILES file may contain a single or many molecules. Hint 2.30Di has tools for reading and writing SMILES files into InsightII. (In the Hint module) pulldown the SMILESBuilder menu to the Get command. Select "smallmol.smi" as the SMILES File. Set Structures to Specified. This activates the Specification parameter which allows an entire name description or a "wildcard" description such as "cyclo*" which would select all molecules in the file that had the string "cyclo" in their name field. Enter "benzene" in the Specification field and press Execute. The 2D SMILES object for benzene is now displayed on the screen. It can be converted to a 3D molecule as described above in step 2.

   InsightII Molecule objects can also be converted to SMILES strings and written to SMILES files. Retrieve cocaine with Molecule Get (top menu bar). Pulldown the SMILES menu to Put. In the Molecule_Spec parameter select COCAINE and in the SMILES File parameter box enter "drugs.smi". Now press Execute to write the first molecule to this file. Get one or more of the other drug molecules and append them to the "drugs.smi" file.

4. Using Sketcher to modify a SMILES 2D Object

   SMILES 2D Objects and Sketch 2D Objects are functionally identical. Thus a SMILES 2D Object can be modified in Sketcher. For example, you can modify the morphine SMILES Object to transform it to heroin.

   

   The necessary changes are replacement of the hydroxyls with acetates. Refer to the Biosym Sketcher manual for specific techniques, but the important first step is to make sure NewSketch is off. Once you have completed the sketch modifications, heroin can be converted to a 3D Molecule Object with 3D_Convert under Sketcher in the Builder module.