Overview

The Structure Activity Landscape Index (SALI) is a numerical approach to quantifying activity cliffs [1] and is described in Guha and Van Drie (2008a). The paper describes an approach to visualize the activity cliffs in a SAR dataset in the form of a network (or graph) termed the SALI network. The original approach was based on static images generated using Graphviz. This visualization tool allows one to interactively explore a SALI network at different cutoff values, allowing one to focus on more or less significant activity cliffs. In addition the application now generates SALI curves (Guha and Van Drie, (2008b)), which allows one to characterize the ability of a modeling protocol to capture the SAR landscape.

It is a modified version of the ZGRViewer application that visualizes networks described in the DOT language. The application has been tested on OS X, Linux and Windows Vista, though it should work anywhere where Java runs and Graphviz has been installed.

Show Recent Updates

Update (07/24/09) - 2.0 uploaded which now supports loading structures from SD files. In such a case, the SD file must have a property representing the activity. Currently, Type 2 curves are not supported when reading from SD files.

Update (06/02/09) - 1.9 uploaded which updates the version of zvtm. Properly handles SVG from recent versions of graphviz

Update (02/13/09) - 1.8.3 uploaded which properly renders aromatic rings

Update (02/12/09) - 1.8.2 uploaded with improved rendering and slightly faster fingerprints

Update (02/02/09) - 1.8.1 uploaded and the single jar file is much smaller than recent versions as it does not include the entire CDK

Update (01/26/09) - 1.8 uploaded and now brings back substructure highlighting. Also atoms are no longer colored, which makes it easier to see the highlighted substructure

Update (01/17/09) - 1.7 uploaded and includes improvements to fingerprint calculation performance and the latest 2D rendering code

Update (01/16/09) - Moved source code to GitHub repository, located at http://github.com/rajarshi/saliviewer/tree/master

Update (09/27/08) - Fixed a bug where the SALI curve UI was not synced with the chemical data that may have been freshly loaded. This update makes sure that when new chemical data is loaded, the SALI curve UI is killed.

Another result of this update is that the jar file is 15MB. This is because we now include the entire CDK library. This is done because the latest version does not properly display 2D depictions on OS X. After this is fixed we will provide a leaner update.

Update (05/13/08) - Updated to use dashed edges between nodes that have a similarity of 1.0

Update (05/08/08) - Updated so that the SALI zoom slider indicates the cutoff at which the network gets so large that layout and rendering might take a long time. Currently, a large network is defined as having 200 or more edges. The cutoff is rounded up to the nearest 10, so it's an approximate indicator

Update (05/06/08) - Fixed a bug which resulted in fingerprint calculation failing since the config file did not have the fingerprint type attribute in it. Also added a dialog to indicate that data loading is complete. Probably should make this into a message on the status bar

Update (04/26/08) - Fixed rendering issues with the latest CDK trunk. Also provided the option to choose which CDK fingerprinter the network should use

Update (04/25/08) - SALI curve functionality is now included in the application. The input format has also been extended to allow specification of one or more predicted property columns

Update (02/29/08) - Depictions of pairs of molecules are now resizable. The application also uses the graph directory specified in the Preferences window. Activities are formatted to two decimal places. Keyboard shortcuts added for loading SALI data and generating the SALI matrix. Also provide a menu option to toggle whether structure differences are highlighted

Update (02/17/08) - Depictions of individual molecules are now resizable

Update (02/16/08) - Structure depictions now display molecule name and activity in the panel itself, rather than just on the title bar. Updated preference pane for SALI operations. You can now alter the length and depth of the CDK fingerprint, highlight differences in the structure for a SALI pair (though for large molecules, MCSS detection may take a very long time) and also define whether a smaller activity value is better (say IC50) or a larger one is better (say -log IC50)

Update (02/15/08) - Updated code to handle molecule names starting with a digit or names containing dashes. The input file format has been changed and the code updated to support it. No longer crashes if activity is missing. Edges corresponding to cliffs for which the similarity equals 1.0, have diamond shaped arrow heads. All other edge will have the normal triangular arrow head.

Update (01/23/08) - Structural differences between pairs are not highlighted due to a bug in the CDK MCSS detection procedure. Once that's fixed, it'll be back

Update (01/22/08) - The program will now highlight the difference in the two structures when an edge is clicked. Note that this seems to be buggy as the MCSS algorithm is sometimes behaving weirdly. Also, edges of the graph are now colored based on the magnitude of the activity cliff, at a given cutoff value. Black is the largest cliff and light grey is the smallest cliff.

Visualizing SALI networks

An example of the interface is here. There are three ways to visualize SALI networks. In all cases, the edges of the SALI network are colored in a grey scale, such that black represents the most significant activity cliff and light grey corresponds to the smallest activity cliff, for a given cutoff

Download

You can get the v2.0 SALI viewer (based on ZGRViewer v0.8) from here and a few example SALI networks are provided below. You'll need to have Graphviz installed on your system for the viewer to work.

You can also get the v2.0 tarball or zip of the sources. Untar the sources and then run ant sali to generate the SALI viewer jar file.

The development version of the soure code is available from GitHub and is licensed under the LGPL.

Usage

If you're running SALIViewer for the first time, you must go to the Preferences window and specify the paths to the various Graphviz executables. If you don't do this you will get an error when you try to generate the SALI graphs
In general, once you have loaded or generated a network you can use the following key/mouse combinations to explore the network Precalculated networks: If you have a precalculated network (see the dot files here) along with the data file you can view the network using the following steps
  1. Start up the viewer (on Unix it should be java -jar sali.jar). You'll need to set some paths in the Preferences window the first time you run the program.
  2. Navigate to File->Open->Open with dot->SVG pipeline and select one of the dot files below
  3. Navigate to SALI->Load Chemical Data and select the a data file (such as mc4r.dat)
Networks on the fly: If you want to generate networks on the fly (using the CDK fingerprint),
  1. Navigate to SALI->Load Chemical Data and select the a data file
  2. Navigate to SALI->Generate SALI matrix
This will bring up the SALI network at a 90% cutoff level. You will also see a slider which allows you to change the cutoff (between 0 and 100). Note that very low cutoffs will generate very large graphs and will take time to process. Useful values of the cutoff are between 25% and 90%

SALI curves: Generation of SALI curves requires that you have generated the SALI matrix as described above. Also, you should have at least one column of predicted values that will be used in the SALI curve calculation. If these conditions are satisfied the following steps will generate SALI curves:

  1. Navigate to SALI>Generate SALI curves
  2. In the popup window, double click on one of the columns representing the predicted values. At this point, these columns will be labeled as Value 1, Value 2 etc.
  3. Click on the Plot SALI curves button
  4. Switch to the Type 1 tab or the Type 2 tab to view the SALI curves
You can try it using a PDGFR dataset. It contains two columns of "predicted" activities - the first such column is simply a jittered version of the actual activity values whereas the second such column consists of uniformly distributed random numbers.

Format

The data files required by the SALI application should be in the form 
SMILES molecule_name activity pred1 pred2 ...
The fields are whitespace (tab or space) separated and lines starting with # are ignored. Names that start with a digit will have an underscore prepended and any dashes in names are replaced with an underscore. If you are using DOT files generated by another application make sure the node names match the molecule names in the data file.

Note that though the terrm activity is used, the program assumes that smaller values of activity are better (i.e., more potent). This is the way one would view IC50's or Ki's. If your data is such that large numbers are more active, you should transform your data prior to using this program or else set the appropriate option in the settings window.

The columns labeled pred1, pred2 and so on are optional. The should represent predicted values of the activities, for use in SALI curve generation. Note that the values do not necessarily have to represent predicted activities. In general they can be any set of predictions or ranks, that are expected to correlate with the observed activity.

Input can also be provided in SD format. In this case, molecule titles are munged as described above. In addition the SD file must have at least one property representing the activity value for the molecule. If multiple properties exist in the file, you will have the option of choosing one.

Datasets

Melanocortin-4 receptor inhibitors

Rajarshi Guha, Indiana University, Bloomington
Last modified: Fri Apr 25 17:41:39 EDT 2008