Control of Hyde affinity calculations handed to user Until now, SeeSAR automatically triggered the Hyde affinity calculations. This could be a long process, particularly when loading a large set of molecules from file, or after making an alteration in the Protein Definition dialog. Now, control is handed over to you the user to decide when the calculation should be triggered. This means large sets of molecules can now be loaded, analyzed and processed (e.g. filtering, calculating properties) before the intensive affinity calculations are run. You can trigger the affinity calculations just for a selection of molecules, for example, or even just for individual molecules in the Molecules table.
Enhanced filter features The collapse and expand buttons (formerly found below the Molecules table) have now been transformed into a filter feature. This feature groups together identical molecules (identified by their unique SMILES), leaving just the molecule with the best estimated affinity as the representative - which is what was previously described as 'collapsing' and was triggered using the collapse button. Also, previously the collapsing or grouping action was always applied before the filters - which was not made apparent with the buttons. Now, this filter is always the last applied. This is clear as the filter is always to the last one shown in the filter panel.
Other improvements On Windows, there was no output from SeeSAR when using the commandline interface - using the commandline on Windows was like flying blind! Just start 'seesar' on the commandline rather than 'seesar.exe' and the problem will be fixed. 'seesar --help' will give you more help getting started.
You can also export the protein ligands when using the commandline interface with the new option '--score-protein-ligands'. This is particularly useful if you need to analyse many protein-ligand complexes.
Covalently bound ligands are now optimized during the Hyde affinity calculation. This allows for a more reliable estimated affinity and is consistent with the treatment of all other molecules. Watch out for more covalent ligand features in following versions!
Finally, you may now load SD files of molecules into SeeSAR that contain many SD properties. SeeSAR will load the properties up to a maximum amount, whereas previously it was not able to load these files at all.
version 4.1 2016-02-10
User-defined visualization settings Up until now, the 3D view settings were optimized for the current scenario, i.e. when you loaded a protein from file or project it was shown in overview, while after selecting a molecule, the view was focused in more detail on the binding site, ... This was quite comfortable - particularly for first-time users - but at the same time limited your freedom to choose your own viewing preferences. As of version 4.1, the user is back in charge. The optimized settings are still shown to start with but now you can choose to show or hide the following:
• Hyde coloring for the selected molecule • torsion coloring for the selected molecule • whole protein • surface for the binding site of the selected molecule • unoccupied space in the binding site of the selected molecule • all waters in the binding site of the selected molecule
The controls can be found in a panel above the 3D view on the main tool bar. There were previously some switches scattered about in different places in SeeSAR to control some of the these view settings - these have now disappeared having been replaced by the cleaner, less cluttered interface in the new panel.
Annotating molecules Many users have requested the option to add comments to specific molecules. We have now implemented this as a new feature that can be accessed via the notepad icon for the currently selected molecule in the table. A sticky note is opened where you can enter your comments for this molecule as free-form text. The annotations are saved along with the user name of the author. Molecules with annotations are indicated in the table by a yellow marker at the top left of the row in the molecule table. If you move the mouse over the marker, the annotation appears as a tool tip making it easy to quickly scan through all the notes in the table. These notes are saved to the project allowing you to keep your ideas and thoughts for later, or also to share them with others.
Enhanced project handling As of version 4.1, SeeSAR will now remind you to save your project if you have unsaved changes before you close SeeSAR or start a new project (either by choosing "New" or "Load" from the Project menu). You now also have the option to "Export" the raw data from your current project to a folder or directory of your choice. This will include the PDB file for the protein, all loaded molecules and any molecules you created using the editor.
version 4.0 2015-11-18
Major release This update of SeeSAR qualifies as major release 4, as several milestones have been achieved with it - namely the integration of the world-reknowned ADME property calculator from Optibrium ™, the display of the protein surface in the 3D view, and an update of the Hyde scoring function. Collectively, these changes have made an update of the SeeSAR storage mechanism necessary, so unfortunately old project files cannot be loaded with this version. We recommend you save your molecules from old projects to file and re-read them with this new SeeSAR version. As an additional bonus feature we implemented the multi-selection of favorites with a simple [Shift] and click. Just try it out, it works as you would expect.
Optibrium As of version 4.0, SeeSAR is equipped with an interface that allows you to benefit from Optibrium's ADME property calculator from within SeeSAR. Any molecule loaded or edited is passed on to the property calculator, which itself applies multiple computational models to determine a variety of ADME properties. By default you'll see:
However, if you have additional models (within the Optibrium framework) you can add those too and have the respective values available at your fingertips. Note that the usage of this feature requires a separate license!
Protein surface The binding site of a protein is oftentimes quite complex making it easy to lose the sense of depth, space and tightness of fit. The protein surface of the binding site is now available to aid with orientation and can be toggled on and off very simply using a switch underneath the molecules table. This way, it is easy to switch between the surface view to find the orientation when you need to and the atom-only view at other times.
HYDE update Hyde is quite sensitive with regards to the numerical stability of the calculation, which we have significantly improved with this update. We also detected a small inaccuracy in the way the coverage of interactions is calculated which has now been corrected. Overall Hyde now has a higher hit rate with respect to the experimental data for high-quality structures and on average avoids overestimating the affinities, i.e. it now provides a more conservative estimate thereby reducing the rate of false positives.
version 3.3 2015-09-04
Considering individual water molecules (watch this!) One of the particular strengths of the Hyde scoring function (and therefore SeeSAR) is its estimation of the effect of water. The whole concept of Hyde is based on the balance of desolvation and interaction. However, as always, the exception defines the rule: Namely, what is true on average for bulk water may be different for individual water molecules. For this reason, Hyde by default explicitly considers water molecules that are particularly tightly bound. Of course, the default may sometimes miss a water that is of particular interest, or take too many into account by including a water that might not be all that stable. Therefore, we have enhanced the Protein Definition dialog so that the user can now have the final say on which waters should be considered and which should be ignored.
Assessing covalently bound ligands (watch this!) Hyde is much liked for its visualization of the individual atom contributions to the overall binding affinity. This version also allows such visual assessment of covalently bound ligands. They are now listed in the Molecules table together with reversibly bound ligands and co-factors. As with all the other small molecules, a focussed view showing the individual atom contributions to binding is shown in 3D when the covalently bound ligand is selected in the table. We don't, however, provide an overall binding affinity for covalently bound ligands since it is meaningless in this context. Editing of covalently bound ligands is currently disabled but is planned as a feature for a later version.
version 3.2 2015-07-24
Utilizing SeeSAR without a protein SeeSAR has grown from a single purpose affinity assessment tool to a multi purpose 3D structural viewer for compound design and prioritization. With this update it is now also possible to use all these nice features for 3D ligand-based projects. You may, for example, visually inspect small molecules alignments. You may filter a hit list by means of calculated and external properties...
Big data booster With version 3.0 we first equipped SeeSAR with database functionality. Version 3.2 comes with a load of performance enhancements that speed up the calculation by up to a factor of 5, now utilizing all available CPUs in your computer even more efficiently.
3D graphics enhancement In this version we updated the graphics support and SeeSAR is now compatible with more graphics cards than ever before. Especially the compatibility with integrated graphics cards (the type most frequently found in laptop computers) - which used to be the major trouble makers - has been greatly improved.
version 3.1 2015-07-10
Working with "big data" With this update we lifted the limit of handling only a maximum of 5000 poses in SeeSAR. We know that a lot of people like to do their compound analysis and prioritization after virtual screening campaigns also with much bigger sets. It is not likely that you will look at more than a couple of hundred poses, however, since the filtering (see also below) is extremely efficient, it provides quite an attractive opportunity to load all your data (not just the top x) and do your prioritization with all properties at hand right here in SeeSAR.
Enhanced filtering Behind the scenes SeeSAR knows so much more about your compounds than what is displayed in the table. The basic stuff like no. of acceptors and donors, rotatable bonds, etc. to do the usual Lipinski-type filtering is of course available, but also more elaborate stuff like the number of hydrogen bonds formed or the number of torsions that lie outside the statistical "norm". All of these are now available for filtering to help you optimally trim down your data to find the really interesting part.
Older project files invalid Please NOTE: SeeSAR project files from older versions are incompatible and cannot be loaded. By default SeeSAR puts a new version in a separate location. So your old version should still be there. If you happen to have lost the old version, read here what you can do about it.
version 3.0 2015-04-14
Major release This update of SeeSAR qualifies as major release 3, since it covers two milestones in its development. So far every SeeSAR session has started from scratch. The only way to retain molecules was to save them to file and re-load them again in a subsequent session. Needless to say that loading meant recalculating all Hyde scores again...
Project files Starting with Version 3.0, SeeSAR allows you to store all session data in a project file. This includes the protein, ligands loaded from file and new (edited) ligands. Resuming your work on a project is now as easy as double-clicking on the project file. As a result, everything just got a hell of a lot faster! Whilst calculating Hyde-scores for say 1000 compounds took around half an hour (depending on your hardware), loading the same information from a project file now takes only a few seconds. Note that you can also generate a project file on the command line, allowing you to outsource the calculation of Hyde-scores to a different machine. This enhancement is also a great way to exchange data and ideas with a colleague! Simply store your SeeSAR session as a project file in a commonly accessible location (e.g. a network drive). Your colleague can take a look with just a double-click.
Hyde update Hyde is quite sensitive with regards to the precise geometry of a binding pose. Even the tiniest difference in a pose can distort an anyway stretched hydrogen bond just so much that it is not recognized anymore - thereby leaving you with a huge desolvation penalty for such atoms, without the gain from the H-bond. This 'sharpness' of Hyde is its greatest strength (for example by highlighting real activity cliffs), but also its greatest weakness (especially if the structure has flaws or is of low resolution). In order to minimize such troubles, we optimize each pose before the Hyde affinity assessment. We improved this optimization significantly. It is now fully flexible and with sharper clash criteria, making it suitable for docked poses as well as edited compounds. All of this as efficient as before, just perfect for interactive use.
version 2.2 2015-03-11
Solution filter Finding interesting solutions in larger sets of compounds has just become much easier in SeeSAR. Compounds can now be filtered based on any available property – allowing you to easily trim down the compound set to the most interesting fraction. As before, you can browse through and sort the remaining table entries to further refine your selection. Properties can be those generated by SeeSAR (such as the Hyde affinity assessment, the torsional strain, TPSA, logP, ...) or alternatively properties loaded from an SD file.
Joined poses We have joined the ligands found in the protein structure, compounds loaded from file and compounds newly generated within the SeeSAR editor into one “super” table and now provide quick-links to the previous view of only those from a certain origin. This allows you to see in one table the bound ligand as a reference, the project compounds and your last round of designs. You can then select your favorites from the entire table and export these (for example for an upcoming team meeting).
version 2.1 2015-01-26
Defining the protein SeeSAR decomposes the contents of a PDB file into chains, small molecules, waters and ions. Until now, users had to accept SeeSAR's default assignments, which is fine in the majority of cases. However, there is no rule without exception, e.g., the peptide inhibitor which is mistaken as a short chain, the small molecule which is actually a co-factor, or the solvent molecule that should be ignored. With this update, SeeSAR allows you to change these default assignments to better handle these exceptional cases, allowing you to categorize a short chain as a bound ligand, or re-assign a co-factor as a permanent part of the protein. You can also eliminate protein elements altogether.
SMILES, PDB and MOL file support We equipped SeeSAR with additional molecule readers that broaden the scope of the application. Aside from standard 3D molecule file formats (SDF and mol2), SeeSAR now supports 1D and 2D file formats as well as reading small molecules from PDB format. If no 3D coordinates are given, SeeSAR will calculate a clash-free, low energy conformation on the fly: with the SeeSAR positioning function you can then place such input molecules in the active site of interest. Amongst other things, this feature facilitates the importing of molecules straight from your favourite chemical drawing program and assessing such structures in in the context of your protein of interest.
version 2.0 2014-12-15
Major release This update of SeeSAR qualifies as a major release, since it covers a milestone in its development. So far SeeSAR was able to assess given poses of small molecules in a protein structure. Starting with release 2.0 SeeSAR can also generate poses. Also note that the Hyde affinity assessment behind the scenes has been further improved by a variety of fixes and small changes for the benefit of more stability of the calculations. These changes will have an effect on the computed scores. If you rely on the scores resulting from a specific version of the tool, we recommend you to keep such older versions of the tool in an archive.
Pose generation SeeSAR assesses the binding affinity based on the given position of the ligand in the active site. New in major release number 2 is the introduction of ligand pose generation directly within SeeSAR. So now you can draw and save a molecule in 2D, load it and have SeeSAR predict both binding poses and the related affinity for those poses. Similarly, if you make a substantial modification to the ligand in the editor, you can now validate the original position by generating new binding poses followed by the affinity assessment.
Ring conformation sampling Significant conformational changes occasionally occurred when ring atoms were modified, reducing confidence in the Hyde estimated binding affinity. We have overcome this by implementing a conformational sampling of ring systems to identify the closest of all energetically favorable ring-conformations.
Stay focused Sometimes, the 'big picture' can get lost while browsing and inspecting poses in 3D – users can now reset to a standard orientation by hitting 'Space' on the keyboard or with a click on the center view button in the utilities area (lower right corner in the 3D view).
version 1.6 2014-11-03
Improved editing One key functionality that was missing from our molecule editor was the ability to manually set atomic charges. We trusted the compute engine underneath (ProToss) to identify the most likely state automatically when optimizing the overall hydrogen bonding network. However, there are always exceptional cases that prove the rule. Now the user has the final say in this by being able to set the charge for individual atoms. Also, within the scope of the application the user setting won't be overwritten. Hotkeys '+' and '-' make these changes happen really quickly.
Improved table handling 2D-depiction: a picture says a thousand words... To quickly eyeball a compound of interest in a SeeSAR table we implemented a feature to show the structure upon mouse-over. Picomolar affinity: one of the main applications of SeeSAR is in lead optimization where it is not uncommon to work with extremely potent molecules. These are now better accommodated by an extension of the estimated affinities into the picomolar range. Pose-specific functions close by: your mouse used to travel a fairly long distance from selecting a compound to the bottom of table to either edit, delete or keep a table entry in view. Now, these buttons appear just underneath the selected row. Show/hide multiple table columns: The context menu to add and remove table headers now stays in view for multiple selections and disappears gracefully if you click on anything else in the application.
version 1.5 2014-09-23
More convenient structure editing In order to make structure editing an even more convenient, swift and fun process, we have added a few new features:
Hotkeys: simply select an atom, then type N to change it to a nitrogen. Obviously this "element change" shortcut works for all one-letter types (C, O, N, S, P, I). Context-menus: simply right-click an atom (or bond) to get the all options to add a new atom (or change the bond type) right there. Draw bonds: simply click & hold on an atom, then drag to a second atom to connect the two with a new bond.
Improved table handling After a virtual screen or docking run, many users will load multiple poses of each of their molecules and then interactively undertake the crucial steps of visual validation and selection. We improved SeeSAR in this regard with two new features.
(1) For a better overview, you can now collapse all poses of one molecule to a single, representative table entry. This will be the best Hyde-scoring pose. Obviously you can also reverse this process and expand the table to show all the poses.
(2) As you go through the table you can mark the poses as favorites that you would like to keep. Following this, you can then choose to export only your favorites.
version 1.4 2014-08-21
Stereo Graphics One of the top features on the wish list was stereo support for polarization hardware. So here it is! To activate stereo mode simply open the settings dialog and check the box for stereo view under Display. You can make adjustments for your eye distance using the slider too. If you use different stereo hardware, please let us know at SeeSAR@biosolveit.de.
UX Further Improved We have taken time to add some more enhanced user experience (UX) features. The main features are:
Re-position labels: Labels (activate this feature using the label icon in the utilities box, bottom right) provide useful information when you click on objects in the 3D view. Now you may drag labels to a different location. This is handy for preparing images to include in presentations and for de-cluttering your view.
Browse ligand table contents without leaving the 3D view: Jump from pose to pose with just a keystroke. Simply use the up/down arrow keys on your keyboard. You can even use the delete key, but watch out as there is no undo yet!
Screenshots made easy A neat new convenience feature has been added to this version. Simply click on the camera icon in the utilities box (bottom right) and save your picture.
version 1.3 2014-07-08
2D visualization of selected ligands When things get complicated in 3D, it may help to drop a dimension: You can now check the 2D formula of a ligand at the bottom left – Prerequisite: the ligand must have been selected with a click on the respective table line. If you would still like to exploit the full 3D view, just hover over the 2D sketch and a collapse icon will appear for your convenience. Please note that during editing, the 2D picture will only be updated upon leaving the editor (shortcut: just press ESC to leave the editor).
Work with your own SD properties Sort, check, visually correlate your own information stored in the SD files you use: Upon loading ligands via the menu entry (the 'L' icon in the upper left), we parse your information and you can add it to the properties table on demand. Additional SD properties are added by selecting them from the property drop-down icon at the far right of the table header. A mouse-over on the table column headers will display your property's full name. So, if you had, for example, your own favorite solubility predictor write its prediction into the SD file, you will now have the value ready to use in the table.
Web settings to comply with corporate environment Your corporate security rules may force you to access the internet through a dedicated computer. You can now specify a proxy to make sure SeeSAR remains fully operational. Please note that the information about the latest updates (displayed when you click on Updates in the Information menu - '?' icon) is obtained from our webpage. If you can’t access this information, this may be a hint that you need to change your proxy access settings.
version 1.2 2014-06-16
See torsions color-coded by statistical relevance We now color rotatable bonds in a simple traffic light scheme to show you whether your torsion angles are similar to those observed in crystals or not. Please note that this is not an energetic statement but rather a statistical one. You can switch between this view and Hyde coloring by using the toggle switch at the bottom left of the table. The colors have the following meaning: • red = seldom, • yellow = occasional, • green = frequent
Show receptor atoms contributing to a Hyde score In SeeSAR, the contributions of receptor atoms are projected onto the ligand atoms, i.e. a red ligand atom can be red because a protein atom is 'unhappy'. To find out which receptor atoms contribute to the ligand atom Hyde score, switch on the label for the respective ligand atom using the label functionality in the utilities area (lower right corner in the 3D view), and click on the eye icon to highlight the contributing receptor atoms.
Quick, convenient distance measurements To speed up measuring several distances from one given atom, you can now view distances with mouseover. Switch on the distance measurement mode using the utilities area (lower right corner in the 3D view), select an atom, and distances to other atoms will appear upon mouseover. If you click on a second atom, the distance measurement will be kept visible permanently.
Lipophilic Ligand Efficiency (LLE) - a new property We have implemented an approximate LLE as an additional guideline property in the tables. The orientation of the thumb symbol indicates whether the LLE is great, good, fair, mediocre, or poor. The calculation is based on the Hyde estimated binding affinity and atomic logP values. The traditional Ligand Efficiency (LE) is still available; you can toggle both properties on/off (just as for all other properties) by using the selection tool at the far right of the table header.
File dialogs now remember your last location When you load protein or ligand data, your last chosen directories will be remembered.
License expiration alert 5 days before your license runs out, an alert dialog will appear when you start SeeSAR. Contact us for an extension at SeeSAR@biosolveit.de.
New version alert When a new version becomes available, SeeSAR will show an alert on the information symbol in the toolbar above right. Click the 'Updates' icon in the information menu to see the new version details. Click on 'Download', or simply go to http://www.biosolveit.de/SeeSAR, and download your new copy from there.
version 1.1 2014-05-19
Conformers color-coded according to crystal torsions For every molecule in a table, a traffic light style flag is now shown. This gives you a feeling for your ligand torsional conformation based on a comparison of the torsions in your molecule with respect to those observed in crystals. Please note that this is not based on energies but on statistical significance. In other words: The more frequently your torsions match those observed in crystals, the more likely the flag will say 'OK.' This is what the color-coding means: • green = most torsions are observed frequently, • yellow = some torsions are seldom or occasionally observed, • red = several torsions are only seldom observed
Visualize the 'explorable volume' of your complex We implemented a swift visualization of where the tightness of fit can be improved, or where you can avoid the horror vacui in your binding site: While you are in 3D edit mode, white 'fog' will indicate empty space in the binding interface.
Multi-file loading You can now load multiple ligand input files at once by performing a multi-selection using the Ctrl/Shift/Apple keys.
Unified labeling Instead of separate labels for Hyde score, atom names, etc., we have now consolidated all this information in a single label per atom. To activate the label, use the label icon in the utilities area in the lower right corner, and click on an atom.
Drag and drop license files License files (*.lic) received from us can be drag and dropped into a dialog opened from the information menu in the toolbar: Information >> License. This way, licensing SeeSAR becomes child's play!