HINT 2.30 Manual: Chapter 4I

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 both SMILES (Simplified Molecular Input Line Entry System) input and InsightII archive 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:

Entering a SMILES string description of a small molecule into Hint.

Reading in small molecule Biosym archive 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 HintGrid Molecule calculation.

Performing the HintGrid calculation.

Display and interpretation of HintGrid 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 HintGrids. 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 HintGrid calculation.

Interpretation of Complementary HintGrid contours.

In Lesson 5, the binding of the A74704 substrate to HIV-1 will be investigated with analytical HintTable and graphical HintGrid 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 HintGrid calculations.

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

Modification of the Protein model.

Lesson 6 demonstrates molecule building using the Hint2.30Di SMILES commands in the InsightII Builder module. SMILES input provides a fast and convenient method for describing the structure of small molecules. In addition, these molecules can be edited with tools in the Sketcher pulldown.

The topics covered in Lesson 6 are:

Entering a small molecule into the Builder module from a SMILES string.

Reading and writing SMILES files.

Editing 2D SMILES/Sketch objects and conversion to 3D molecule objects.

Lesson 7 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 7 are:

Identifying important water molecules in a complex biomolecular structure.

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