Pharma RQSAR Panel

In this panel you can create a QSAR model for the activity as a function of the kind of R-group at each attachment position, and display the results qualitatively in terms of increasing the activity, decreasing the activity, or little effect on the activity.

Using the Pharma RQSAR Panel

The QSAR model is built using counts of pharmacophore features present in the R groups at each position as the independent variables. The pharmacophore features are the standard features used in Phase QSAR models: hydrogen-bond acceptor (A), hydrogen-bond donor (D), hydrophobic (H), negatively-charged (N), positively-charged (P), and aromatic (R).

A partial-least-squares (PLS) procedure is used to fit the data, assigning 75% of the data to the training set and 25% to the test set at random. The fitting is repeated many times, each time picking the best model that does not overfit the data (which occurs when the standard deviation of the fit is smaller than the error in the property being fit). The mean of the coefficients from all of these trials is used to determine whether a feature at a given position contributes significantly to the property, either positively or negatively: if the absolute value of the mean is greater than the supplied cutoff, the contribution is considered significant.

When the calculation finishes, the attachment positions are labeled with a list of letters representing the pharmacophore feature types, colored by significance: red for significant positive contributions, blue for significant negative contributions, and gray for insignificant contributions. If a pharmacophore feature is absent from an attachment position, a lower-case letter is used instead of an upper-case letter.

To generate a QSAR model:

1. Choose a property from the Property option menu
2. Specify the error in the property in the Error box.
3. Specify the cutoff for significant contributions in the Importance cutoff box.
4. Click Start

Pharma RQSAR Panel Features

• Display area
• Property option menu
• Error option menu
• Importance cutoff option menu
• Key to annotations section
• Start button
• Display Details button
• View Atomic Contributions button
• Export CSV button
• Export Image button

Display area

Displays the core, annotated at each attachment point with the pharmacophore feature types and their contribution to the selected property. The annotation consists of the six letters of the pharmacophore feature types. Features that were not found at a given attachment point are shown in lower case. Features that have significant negative contributions to the property are colored blue and placed on the left. Features that have significant positive contributions to the property are colored red and placed on the right. Features that have insignificant contributions are colored gray and placed in the middle.

Property option menu

Choose the property used for the activity from this option menu. A message is displayed to the right, indicating how many of the structures analyzed have the selected property.

Error option menu

Enter the estimated error in the values of the property in this box. The value can be derived however you like. It is used to check for overfitting in the PLS procedure: the number of factors used is the largest number at which standard deviation of the regression is larger than the error given in this box.

Importance cutoff option menu

Specify the cutoff on the mean value of the PLS coefficient for a pharmacophore feature to be considered to significantly affect the predicted property. The units of the cutoff are the same as those of the property.

Key to annotations section

The key to the annotations is described in this section. The letters that represent the pharmacophore feature types are listed with their definition.

Start button

Start building the QSAR model. When the model is built, the structure is annotated with the feature types, colored according to their contribution to the selected property.

View Atomic Contributions button

View contributions from each atom to the predicted property. Opens the Pharma RQSAR - Atomic Contributions panel.

Display Details button

Display a summary of the information obtained from the partial-least-squares procedure. For each pharmacophore type, the minimum, maximum, mean, and standard deviation for the PLS coefficient is given, and the assessed effect on the activity is listed, as weak, positive, or negative.

Export CSV button

Export the information displayed in the summary panel to a CSV file. Opens a file selector, in which you can navigate to a location and name the file.

Export Image button

Export an image of the annotated structure in TIFF, JPEG, or PNG format. Opens a file selector, in which you can choose the format and name the file.

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