HINT 2.30 Manual: Chapter 6S

Tutorial

In this tutorial you perform several HINT calculations designed to acquaint you with the most commonly used features and calculation strategies of HINT.

In Lesson 1, you calculate the LogP (log of the partition coefficient for water/octanol) for several small molecules using SYBYL .mol2 files. LogP, also referred to as the hydrophobicity, is a key parameter for drug design and QSAR (Quantitative Structure Activity Relationships). The step of calculating LogP as demonstrated in this lesson is the beginning point for all HINT calculations.

The topics covered in Lesson 1 are:

Reading in small molecule SYBYL .mol2 files.

Setting desired Partition calculation parameters.

Performing the HINT partition calculation.

Lesson 2 illustrates how to calculate and display three-dimensional HINT hydropathic contour maps for small molecules.

The topics covered in Lesson 2 are:

Setting up parameters for a HintMap Molecule calculation.

Performing the HintMap calculation.

Display and interpretation of HintMap contours.

In Lesson 3 you Partition a macromolecule (protein) using the HINT dictionary method and calculate/display the three-dimensional hydropathic map of the protein. The molecule studied in this lesson is HIV-1 protease. The most interesting structural feature of this protein is the obvious active site guarded by the two "flaps". In later lessons we will perform further HINT calculations on HIV-1.

The topics covered in Lesson 3 are:

Reading in a Protein-Data Bank format file.

Performing the HINT Dictionary Partition calculation.

Lesson 4 demonstrates the technique of Complementary HintMaps. In terms of drug design, this action can be thought of as finding a "key" for the known receptor "lock". The HIV-1 protease structure, in the vicinity of the active site, will be probed by HINT to propose the three-dimensional hydropathic structure of potential substrates. One known substrate, A74704, whose bound structure in HIV-1 is known, will then be compared to the HINT "key" map for HIV-1.

The topics covered in Lesson 4 are:

Setting up and performing a Complementary HintMap calculation.

Interpretation of Complementary HintMap contours.

In Lesson 5, the binding of the A74704 substrate to HIV-1 will be investigated with analytical HintTable and graphical HintMap InterMolecular calculations. This substrate binds with an affinity of 4 nM, and has been used as a lead compound for further research in inhibiting HIV-1. One type of result from HINT calculations of this type are obvious suggestions for improvement of the molecular model. In this lesson you will see an acidic protein residue that perhaps should be modeled as being protonated in the bound complex.

The topics covered in Lesson 5 are:

Preparing small molecule coordinate data read in a foreign format for HINT calculations.

Setting up and performing InterMolecular HintTable calculations.

Setting up and performing InterMolecular HintMap calculations.

Interpretation of HINT interaction contours in terms of analytical results from a HintTable calculation.

Modification of the Protein model.

Lesson 6 demonstrates using HINT parameters and fields in the 3D QSAR (CoMFA). The example in this lesson is contrived, in that the HINT 3D hydropathic field is used to model the HINT calculated LogP value. The example, however, demonstrates most aspects of the use of HINT with CoMFA.

The topics covered in Lesson 6 are:

Using HINT to fill a QSAR table column with hydrophobicity (LogP) values.

Using HINT to fill a QSAR table column with a hydropathic field similar to the standard CoMFA electrostatic and steric fields.

Adjusting HINT field setup parameters to modify a 3D QSAR model.

Analyzing 3D QSAR results with contour maps.

Lesson 7 gives a brief example showing how HINT scoring and/or mapping techniques may be used to analyze the results of a SYBYL dynamics or conformational search calculation. In the example a complex, HIV1 with A74704 is examined at various steps of a dynamics calculation. The topics covered in Lesson 7 are:

Using HINT to fill a QSAR table column with InterMolecular HINTScore values.

Analysis of MSS results.

Lesson 8 shows how you can use the HINT Small Ligand Optimization command to find the best location and orientation for a crystallographically determined water molecule at the active site of HIV-1 protease. The topics covered in Lesson 8 are:

Identifying important water molecules in a complex biomolecular structure.

Improving the water's interactions with both the protein and inhibitor.