BioSolveIT SeeSAR 4.0 Final

SeeSAR is a software tool for interactive, visual compound prioritization as well as compound evolution. Structure-based design work ideally supports a multi-parameter optimization to maximize the likelihood of success, rather than affinity alone. Having the relevant parameters at hand in combination with real-time visual computer assistance in 3D is one of the strengths of SeeSAR.

Stimulating exploration with SeeSAR, we have embarked on persuing a new cheminformatics compute paradigm of "Propose & Validate" with these first four themes accomplished so far:
1. affinities:
We implemented sophisticated graphics to visualize atom-based affinity contributions; that allow for a rough estimate of the ΔS / ΔH -split of the Free Energy. (This is an ongoing co-development between BAYER, the University of Hamburg and BioSolveIT.)
2. phys-chem properties:
Relevant parameters are computed on-the-fly or imported to be taken into consideration throughout the design process.
3. torsional 'heat':
Torsional statistics analyses (developed between Hoffmann-LaRoche and the University of Hamburg); is readily available via intuitive color-coding.
4. 'explorable space':
A tight fit is the prerequisite for both, affinity and specificity. Therefore, as guidance for the user, efficient computation combined with refined graphics provides on-the-fly visualization of gaps in the binding interface and positions where a tighter fit is likely to be gained.

Whats New in version 4.0
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:

• logP
• logD @ pH7.4
• logS (thermodynamic, intrinsic aqueous solubility)
• logS @ pH7.4 (in phosphate buffered solution)
• Blood-brain barrier penetration (log([blood]:[brain])
• hERG inhibition (pIC50)
• CYP2C9 affinity (pKi)
• Human intestinal absorption (HIA) classification
• Blood-brain barrier penetration classification
• CYP2D6 affinity (pKi) classification
• Plasma-protein binding classification
• P-gp transport classification

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.

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