HINT 2.30 Manual: Chapter 6S

LESSON 1: Calculation of LogP for Small Molecules

  1. Invoke SYBYL

    To begin this lesson, type source $HINT_DEMO to the unix cshell prompt. This script makes a new directory in your account titled "hint2.2S_demo" which has soft links to the master HINT tutorial directory. Type cd hint2.2S_demo to change to this new tutorial directory. Then enter the command sybyl to load and run SYBYL.

  2. Partition small molecules using SYBYL .mol2 files

    From the menubar go to the File pulldown and select the Read... command. A list of available files in the current directory appears in the dialog box. If you select Molecule from the File Type menu, the directory list will be filtered (by filename extension) to include only files that are likely to be molecular data. Select cocaine.mol2 and press the OK button. The COCAINE molecule should be displayed in the SYBYL M1 molecular display area.

    Now, pulldown eslc to Hint; select Partition followed by Molecule.... This invokes the Partition Molecule dialog box. First we must select the Atoms... to be partitioned. In the Atom Expression dialog box verify that M1 is the chosen molecular area and press the All push button to select all atoms of COCAINE. (Press OK.) 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 Essential, however, if you are going on to Lesson 2. We will discuss the ramifications of Hydrogen Treatment in Lesson 5.

    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. Press OK to perform the Molecule Partition calculation. The LogP of cocaine (ion) is calculated to be 1.10.

    Repeat the calculation (Step 2) 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

    MoleculeLog P
    cocaine 1.10
    dopamine -1.71
    acetylcholine -1.25
    aspirin -0.24
    morphine 1.55
    17-Beta-estradiol 4.89