LESSON 1: Calculation of LogP for Small Molecules

1. Invoke InsightII

   To begin this lesson, define the Hint commands by typing source $EDUSOFT_ROOT/eslc/config/cshrc_hint at the unix cshell system prompt. Next type source $HINT_TUTORIAL, This cshell script makes a new directory in your account titled "hint2.3I_tutor" which has soft links to the master Hint tutorial directory. Type cd hint2.3I_tutor to change to this new tutorial directory. Then enter the command DEFINE_HINT to set the path for using the Hint object library rather than the default Biosym/MSI object library. Next type insightII at the prompt to load the special version of InsightII that contains the Hint module. It takes a few moments for the program to load.

2. Select the Hint module

   From the Module pulldown (Biosym logo) on the top menu bar, select Hint!. The Hint menu is displayed on the lower menu bar.

3. Partition small molecules using SMILES input (option 2.30Di users only)

   From the Hint menu bar, go to the Partition pulldown and select the SMILES command. When the Partition SMILES parameter box appears, you may begin entering molecules for Log P calculation. The SMILES notation is a simple method of describing molecular structure and connectivity in a compact form. It is fully described in (Weininger, D. J. Chem. Info. and Comput. Sci. 1988, 28, 31). Hint uses the Daylight Toolkit to interpret the SMILES code. This is the most advanced SMILES interpreter available. A few sample molecules and their SMILES notations are listed below. To calculate LogP for these molecules, choose Enter String as the SMILES Source, enter the SMILES String exactly as listed, Give a SMILES Object name or accept the default. Then select Execute to perform the Log P calculations. The results will appear in information boxes in the center of the screen. Alternatively SMILES strings in ASCII files can be Partitioned. Choose From File as the SMILES Source. The file "smallmol.smi" has a few SMILES molecules that you can experiment with. Note the Structures option: if Specified is selected, then specific molecules from the SMILES file can be chosen, either with a complete or a partial (supplemented by wildcard) Specification.

   Practice SMILES Strings
   
   Molecule       SMILES String           LogP
   
   methanol       CO                      -0.750
   acetone        CC(=O)C                 -0.240
   benzene        c1ccccc1                 2.130
   t-butanol      CC(C)(C)O                0.430
   phenol         c1ccccc1(O)              1.460
   amphetamine    c1ccccc1CC(N)C           1.340
   
   

4. Partition small molecules using Archive files

   From the top (Viewer) menu bar go to the Molecule pulldown and select the Get command. A list of available Biosym Archive files appears in the Value Aid list. If Get File Type is not Archive set it to this value. Select cocaine.car and press the Execute button. The COCAINE molecule should be displayed in the viewport.

   Now, pulldown Partition and select the Molecule command from the Hint menu bar. Note that the Molecule is defined as COCAINE in the Partition Molecule parameter block. For small molecule partition calculations, the Partition Method should be set to Calculate. The Partition_File option gives you an opportunity to write an ASCII file containing the output from the Molecule Partition calculation. Leave this parameter off. Hydrogen_Treatment dictates how Hint will calculate parameters for the defined hydrogens in the current molecule. For the purposes of (only) calculating LogP your choice is not important as similar (but not neccessarily identical) results will be obtained with all three options. Choose Polar_Only, however, if you are going on to Lesson 2. We will discuss the ramifications of Hydrogen_Treatment in Lesson 4.

   Polar_Proximity is the method chosen to correct LogP for the effects of proximal polar groups within the molecule. It has been observed that there is a synergistic damping of the solubility properties of molecules containing multiple polar groups. For almost all cases, choose the Via_Bonds method. This is most consistent with the Leo fragment method of LogP estimation. Through_Space uses a distance-dependent function to correct for polar proximity; this method may be of limited use for some larger molecules that have significant intramolecular interactions, but is not recommended for small molecules. Select the Execute button to perform the Molecule Partition calculation. The LogP of cocaine (ion) is calculated to be 1.102.

   Repeat the calculation (Step 4) for some of the other molecules listed in the table below. Note that these molecules have been modeled with specific ionization states (e.g., cocaine salt, aspirin ion). Thus the LogP result that HINT reports is specific to that ionization state and may not agree with literature results.

HINT Log P

Molecule               Log P

cocaine                 1.10
dopamine               -1.72
acetylcholine          -1.25
aspirin                -0.24
morphine                1.54
17-Beta-estradiol       4.88