Macs in Chemistry

Insanely Great Science

drug design

SeeSAR Updated

 

SeeSAR has been updated to version 7. There is a review of an older version of SeeSAR here. However SeeSAR is a constantly evolving and improving piece of software.

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.

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This update includes

  • Full integration of ReCore functionality. Now - besides fragment-replacement, joining and merging of fragments is also possible. In addition, you can fine-tune results delivered by ReCore using pharmacophore filters.
  • Editing turns into full-blown designing. Besides atom by atom changes you may now add the most common rings with just one klick. So large changes can quickly be made to molecules and this in itself necessitates another new feature — namely that multiple poses are generated based on a superposition of the maximum common substructure.
  • Display of torsion distribution. On the one hand, we have now integrated the latest update of the database of torsion angle distributions from the CSD, while on the other, it is now possible to view the torsion angle distribution for a particular rotatable bond.
  • Miscellaneous enhancements. The SDF export covers your particular selection of favourites and any comments attached to a molecule. For a numerical filter it is now possible to define both a lower and upper bound. Last but not least, besides distances, you may now measure angles and torsions.

Comments

SeeSAR 6.1 released

 

SeeSAR 6.1 has been released, looking at the release notes there are a couple of useful additions.

  • Multiple protein alignment, Since version 5.6 it has been possible to load and work with multiple proteins. So far this feature could only be utilized with pre-aligned structures. Now you can do the 3D alignment in SeeSAR itself. The alignment is based on and optimized according to the superposition of related active sites. Therefore, once you have selected a binding site, just one click is all that is needed to superpose all related binding sites at once. Note that the superposition is limited to highly homologous proteins (>90% sequence identity).
  • SeeSAR/StarDrop interface. We have implemented a new function that greatly improves the interaction between the two software packages. Using the option in the molecule table toolbar, you may now transfer all (or the subset of favorite) molecules directly to StarDrop, which is launched automatically. This interface is supported in StarDrop starting with the recently released StarDrop version 6.4 and StarDrop now analogously supports launching and submitting data to SeeSAR. So it is in fact possible to transfer data back and forth and exploiting maximum synergy to make the best of both worlds. Note that this feature may require a few adjustments in your SeeSAR settings to become fully functional.
  • Shortcut to copy protein ligands. Usually among the first tasks after loading proteins is to copy the related protein ligands to the molecules table for further processing (docking, editing, re-scaffolding, etc.). Especially with multiple proteins this turned out to be a quite cumbersome procedure. Therefore we have implemented a shortcut function in the toolbar of the proteins tab to copy all protein ligands at once to the molecules table. Note that this function will copy all ligands irrespective of their position in relation to the common binding site that is used in the context of the molecules table. So some of the copied ligands may lie well outside the common binding site.

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.

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Comments

Launch of Flare

 

Cresset just announced the launch of Flare a new software tool to aid the understanding of protein ligand interactions.

Key new technology available in Flare 1.0:

  • Visualize the electrostatics of the protein active site using protein interaction potentials
  • Calculate the positions and stability of water in apo and liganded proteins using 3D-RISM
  • Understand the energetics of ligand binding using the WaterSwap technique.

Flare-GUI

Flare uses the XED force field to calculate a detailed map of the electrostatic character of the protein active site. The interaction potentials provide you with vital knowledge of the fundamental processes that underlie ligand-protein binding, helping you to perfect the design of new molecules. The position and energetics of water molecules in and around the active site is of crucial importance in understanding ligand binding. Knowledge of which water molecules are tightly bound and which are energetically unfavorable can give valuable insights into structure-activity relationships and help you to decide where to place ligand atoms. Cresset’s 3D-RISM analysis utilizes the advanced inter-molecular descriptions of the XED force field to give you a water analysis you can trust.

Flare is available for Mac OSX, Linux and Windows and free evaluation is available


Comments

Predict skin toxicity

 

Pred-skin is a new mobile app for predicting skin toxicity. Pred-skin is a web app that accesses a web service http://www.labmol.com.br/predskin/ for the calculation and thus requires internet access. The web service also allows bulk predictions.

Chemically-induced skin sensitization is a complex immunological disease with a high impact on the quality of life and working ability. Despite some progress in developing alternative methods for assessing skin sensitization potential of chemical substances, there is no single in vitro test that correlates well with human data. Machine Learning (ML) models provide a rapid screening approach and contribute valuable information for the assessment of chemical toxicity. The Pred-Skin App is an alternative method for assessing skin sensitization potential of chemical substances.

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Full details are in the publication Pred-Skin: A Fast and Reliable Web Application to Assess Skin Sensitization Effect of Chemicals DOI There are many more mobile apps available for science on the mobile science website.


Comments

SeeSAR Updated

 

This new version of SeeSAR an interactive tool for designing/improving ligands for drug discovery. This update comprises another milestone in the evolution of this lightweight 3D modeling package, namely its ability to manage multiple protein structures simultaneously. Oftentimes, you may need to take account of multiple, related protein structures, perhaps either to identify the differences while aiming to achieve specificity, or – just the opposite – to find commonalities, such as when you are trying to ensure all variants of a protein will likely be inhibited. In this first implementation of the multi-protein feature, it is not yet possible to align protein structures but it is necessary to work with pre-aligned structures. Loading multiple proteins

Loading a protein does not now start a new project, but instead the new protein is simply added to a table of loaded proteins. In order to visualize the binding of ligands from the protein file, first select the protein of interest and then select one of the ligands listed in the table. As before, any of these bound ligands can be copied to the molecules table with a click on the molecule icon in the ligand table row. Handling multiple proteins

By default, the proteins chains are colored according to the same coloring scheme as before, with each chain in a different color. In the protein table you may set a unique color for a protein to ease identification that will be used for all components of that protein. If you edit a protein, the edited version of the protein will simply be appended to the table without overwriting the original. It is of course also possible to delete proteins from the table. Finally, you may choose the protein to be used for defining a common binding site from the table, just click the icon to start the binding site definition. Once a common binding site has been defined, a little binding site icon indicates which protein was used. Note that only this particular protein is used for the generation of poses, as well as for optimization and affinity estimation, i.e. the Hyde atom coloring on molecules is shown with respect to this protein.

Viewing multiple proteins

Once a common binding site has been defined on one protein, the binding site itself is shown in greater detail. Now however, the regions of the other proteins in the vicinity of the common binding site are also shown in greater detail. This allows you to see the detail you need when seeking out differences or commonalities but the view may, however, become a little crowded. An enhanced menu under the protein visualization icon allows you to switch on and off different protein components (secondary structure, binding site amino acids, ligands, waters and metals) individually or as a group, and you may also change the visibility of entire proteins at once, all making handling of the view very flexible depending on your needs.

Other improvements

We have fixed some seldom occurring but still irritating issues with the 3D editor and also implemented the possibility to restrict the number of CPUs that SeeSAR may recruit for its computation on the command line. The option --thread-count allows you to limit the number of parallel compute threads as best suited. This feature is particularly useful if you run SeeSAR on a cluster which is controlled by a batch queuing system.

There is a review of an earlier version of SeeSAR here.


Comments

SeeSAR Updated

 

A new version of SeeSAR is now available for download.

Version 5.5 includes several new features and has undergone some tweaks under the hood to improve speed.

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From the release notes:-

2D browsing featuring in-view molecule properties
To further enhance the 2D browsing, we have added an illustration of the molecules' key properties in the form of a radar plot. A thumbnail of the plot is embedded in each of the 2D molecule pictures, providing a quick overview. it enlarges upon mouse-over and provides access to the configuration dialog. Add or remove property-axes, optionally fine-tune the scales and set 'desired' value ranges. A hit or miss of the latter is indicated by green or red dots on the corners of the color-coded characteristic shape of the molecule on the plot (the greener the better).
Detecting novel/unoccupied binding sites
Now SeeSAR can search your protein for unoccupied pockets based on the world-renown DoGSite-Algorithm. You may then select these to become the binding site, within which to generate poses and calculate binding affinities for your molecules. The new binding site definition feature lets you either use a selected molecule from the table (based on a 6.5Å shell around it, as before) or will detect and visualize empty pockets for you to select instead.
Multiple reference molecules
The reference molecule in SeeSAR always stays in view even when you select other entries from the molecule tables. Now, however, you are able to set - and keep in view - as many reference molecules as you like. Either set them individually - in the selected molecule menu (as before) - or mark several as favorites and set them all as references at once, via the new menu button below the table.
Multiple core replacements with just one click
With the new multiple solutions button for ReCore in the molecule editor, brainstorming new scaffold ideas became yet easier. You can now generate 10 new alternative core replacements at once. The new molecules are saved directly to the table so that you can immediately see their estimated binding affinity and view all structures in 2D at a glance.


Comments

SeeSAR 5.4 released

 

There has been a new update to SeeSAR, this latest update brings.

2D molecule browsing - time to look at things from a different angle

While the molecule table offers great functionality for prioritizing compounds based on the data, it does not provide an overview of the molecules themselves. This release, however, sees the introduction of 2D molecule browsing. The table now offers two views - the one you already know and a 2D browser - flick between them using the switch below the table. Both views are always kept in sync so if you add a filter or sort etc. the 2D browser will show you the same result in the same order as the table. Also try expanding the table area to see how more molecules fit into the view.

Fantastic new 3D graphics features

This release also brings with it some great new 3D graphics improvements. As much as we all like visualising the binding site surface, it lay often times in the way… The binding site surface can now be switched to transparent allowing you to see through it and therefore making the analysis of the binding site and molecules within much more comfortable. Also, the feeling of depth in the 3D view has been improved to help orientation - a so-called "fog effect" fades out the protein and molecules that are further away to bring the foreground more into focus.

Persistent amino acid labels and better view of reference

So far, labels on binding site components unfortunately disappeared when browsing through different molecules in the table. Now amino acid, co-factor and water labels remain present if you change to a different molecule in the 3D view and even if you enter the molecule editor. The view of the reference compound has also been improved. For better visibility, the thickness of the bonds has been increased and instead of coloring the whole molecule in a uniform blue color, only the carbon atoms are colored blue so that hetero atoms can be distinguished more easily.

There is a review of an early version of SeeSAR here.


Comments

Cheminformatics for Drug Design: Data, Models & Tools

 

This is a joint meeting Organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group. To be held at Imperial War Museum, Duxford, UK, on Wednesday 12 October 2016.

There is an interesting line up of speakers and exhibitors and a chance to have a look around the aerospace museum. More details and the booking form are here https://www.soci.org/Events/Display-Event?EventCode=FCHEM481.

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Comments

SeeSAR Update

 

A new update to SeeSAR has been released. The most exciting new feature it the new 2D/3D-sync. Atoms in the 3D and the 2D representation will now simultaneously be highlighted, giving you full flexibility. In the editor you may choose to select atoms and bonds now also in 2D. Particularly handy here is the lasso-style selection.

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.

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Other cool features are:

  • manually adjust conformations after editing
  • key information of a PDB file at hand in the protein table
  • text labels that automatically change color according to your choice of background
  • and last but not least a floating licensing option

There is a review of an earlier version here.


Comments

Cheminformatics for Drug Design: Data, Models & Tools

I’ve just heard that the poster deadline for the Cheminformatics for Drug Design: Data, Models & Tools meeting organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group has been extended.

Imperial War Museum, Duxford, UK Wednesday 12 October 2016

Full details are available here https://www.soci.org/Events/Display-Event?EventCode=FCHEM481

Sounds an excellent meeting and you will have a chance to look around the aircraft at the Duxford Imperial War Museum.

Comments

SeeSAR 5.2 released

 

SeeSAR has been updated to 5.2, with loads of features that many people had on their wish list

  1. ReCore-improvements: auto-avoid clashes and duplicates; load and install the index from within SeeSAR
  2. Simplify binding mode visualization, e.g. by hiding all amino acids not interacting with your compound
  3. Color coded protein surface: by either element, depth of the pocket, hydrophilicity
  4. For more details and all improvements see: http://www.biosolveit.de/SeeSAR/changes.html

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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.


Comments

SeeSAR Updated

 

The major release version SeeSAR 5.0 just came out. It brings along a number of terrific new features:

  • The user is now in charge to define a common binding site, which makes comparing different poses much simpler and enhances the speed of display;
  • Editing and the Hyde visual affinities have so far been completely separate. Now you can easily switch back and forth between these two essential tasks;
  • Editing covalently bound molecules is also possible with this new version:

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Comments

Cheminformatics for Drug Design: Data, Models & Tools

 

A joint meeting Organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group

More Details and booking form

A4 Cheminfo flyer


Comments

Spark V10.4 released

 

Cresset have just announced the release of Spark V10.4.

Spark finds biologically equivalent replacements for key moieties in your molecule. Whether your goal is R-group exploration, patent busting or scaffold hopping, your results will include structures you have thought of yourself, plus new structures that make chemical sense and are totally unexpected.

The new features include:-

  • New Cresset reagent databases derived from eMolecules’ building blocks, replacing previous reagents based on ZINC, include availability information for every result
  • New analysis of the conformation of every result using the Torsion Library method of Guba et al. that is based on an analysis of the Cambridge Structural Database (CSD)
  • New configurable connection to external REST service for properties that enables you to add your own data and properties to the Spark experiment
  • Improved Radial Plots to support enhanced multi-parameter optimization.

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Comments

ChEMBL Models iPython Notebook

 

With the release of ChEMBL 21 has come a set of updated target predicted models.

The good news is that, besides the increase in terms of training data (compounds and targets), the new models were built using the latest stable versions of RDKit (2015.09.2) and scikit-learn (0.17). The latter was upgraded from the much older 0.14 version, which was causing incompatibility issues while trying to use the models.

I've been using the models and I thought I'd share an iPython Notebook I have created. This is based on the ChEMBL notebook with code tidbits taken from the absolutely invaluable Stack Overflow. I'm often in the situation where I actually want to know the predicted activity at specific targets, and specifically want to confirm lack of predicted activity at potential off-targets. I could have a notebook for each target but actually the speed of calculation means that I can calculate all the models and then just cherry pick those of interest.

Read on…


Comments

SeeSAR Updated

 

SeeSAR Version 4.2 just came out! The main new features are

  • You now control when the compute-intense Hyde-calculation runs, 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.
  • Much improved version of grouping all poses of the same molecule

Version 4.2 comes with a load of minor improvements, particularly for the command line use. The full release notes are here.

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I've been following this software since it was first released and there is a review here, every update brings useful features. It is well worth downloading the free 1 week trial to have a look at.


Comments

StarDrop 6.3

Optibrium have announced the latest update to the StarDrop application. The highlight for version 6.3 is perhaps the integration of SeeSAR an intuitive structure-based design tool.

The new SeeSAR module for StarDrop provides a state-of-the-art and scientifically rigorous approach to understanding the binding of compounds in their protein targets in 3D. Users can import ligand and protein structures, derived from crystal structures or predicted with any docking software, and visualise the key interactions driving potency. This is seamlessly linked to StarDrop’s chemoinformatics methods based on 2-dimensional (2D) compound structure and its unique Card View approach to interpreting the resulting structure-activity relationships.

A preview of StarDrop 6.3 will be on show at the American Chemical Society National Meeting, 13th-17th March 2016.

There are reviews of SeeSAR and StarDrop in the reviews section.


Comments

SeeSAR updated

 

SeeSAR has been updated. SeeSAR is a software tool for interactive, visual compound design and prioritization. There is a review of an earlier version here

Release Notes

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:

• logP
• 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.


Comments

PolyPharma app updated

 

The iOS app PolyPharma has been updated. PolyPharma uses structure activity relationships to view predicted activities against biological targets, physical properties, and off-targets to avoid. Calculations are done using Bayesian models and other kinds of calculations that are performed on the device.

More details are available in this presentation.


Comments

An early Christmas present from Chemical Computing Group

 

Chemical Computing Group have just released an up date to MOE, version 2015.10 includes:-

Protein-Protein Docking

  • Generate docked poses using FFT followed by all atom minimization
  • Define receptor and ligand sites to focus docking
  • Automatically detect antibody CDR sites

Integrated Alignment, Consensus and Superposition in the Sequence Editor

  • Manipulate multimeric protein sequences using split side-by-side Sequence Editor panes
  • Use dendrograms to visualize pairwise similarity, identity and RMSD relationships
  • Select residues based on plotted values using resizable sequence editor plots

Distributed Pharmacophore Searching

  • Run pharmacophore searches on a cluster directly from MOE GUI
  • Perform fast corporate database searches
  • Access multiple databases stored on a central server

Covalent Docking and Electron Density Docking

  • Use reaction-based organic transformations to covalently docking
  • Minimize ligand strain energy while maximizing ligand fit to electron density
  • Run docking through an enhanced streamlined scenario-based interface

Extended Hückel Descriptors and pKa Model

  • Compute molecular properties such as logP, logS and molar refractivity
  • Determine populations of ligand protonation states at a given pH
  • Calculate the pKa and pKb of small molecules

13C NMR Analysis

  • Apply QM conformation refinement to calculate 13C NMR shielding
  • Convert computed shieldings and predict 13C NMR chemical shifts
  • Compare computed chemical shifts to experimental shifts for structure determination

I'll write a review in the New Year.


Comments

SeeSAR 4

 

SeeSAR has been updated, the description below gives full details.

This update of SeeSAR qualifies as major release 4, as several milestones have been achieved with it - namely the integration of the world-renowned 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.

Comments

CLC Drug Discovery Workbench updated

 

CLC Drug Discovery Workbench 2.5 has been released.

  • Protein optimizer: New interactive tool invoked from the side panel in molecule projects. It allows for manual mutation and repair of amino acids, flipping of side chains, manual selection of side chain rotamers, and local adaption of protein structure to point mutations.
  • Ligand optimizer: The ligand optimizer allows now for custom modification and creation of ring structures. 3D molecule viewer:
  • Molecule surfaces can now be transparent, A clipping plane can cut into surfaces and secondary structures, Options for creating atom groups and visualizing hydrogen bonds have been improved

CLC Drug Discovery Workbench is your virtual lab bench. It gives you access to atomic level insights in protein-ligand interaction, and allows new ideas for improved binders to be quickly tested and visualized.

Comments

Using Torch

 

A nice blog post describing the use of Torch to analyse molecules

The choice of which molecule(s) to progress into synthetic chemistry depends on a number of properties – potential for activity, logP, MW, flexibility etc.. The problem faced by most project teams is one of balance in that although there is usually an ideal range of values for each property, not every property is equally important. For example, the ideal may be to have MW<500 and logP<3 but there may be more tolerance for a high MW if logP is well within range.

Comments

SeeSAR Updated

 

A new version of SeeSAR is now available. SeeSAR is intended as an interactive tool for designing/improving ligands for drug discovery. In the SeeSAR review I write about an earlier version one of the issues I flagged was a problem when dealing with covalently bound ligands, this has now been addressed.

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.

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This new version also has the the ability to choose which water molecules to consider, this way overwriting the Hyde-default in cases where you know better.

Comments

Brood v3.0 released

 

OpenEye have announced the release of Brood v3.0 a bioisostere replacement program.

  • Custom Fragment Conformations: Fragment geometries can now be derived from any 3D source, including the CSD.
  • Fragment Joining and Cyclization: Finding a fragment to bridge two disconnected molecules or cyclize a molecule is now directly supported.
  • Improved Filter Properties: Property filters can now have both minimum and maximum values.
  • Mapping Fragments to Source Molecules: Molecules BROOD constructs now include the source molecule from which the replacement fragment is derived.
  • Results Navigation: BROOD’s results navigation tool has been redesigned to be more intuitive, giving users an easy way to quickly explore the clustered and aligned analog molecules.

Full details are available in the release notes.

Comments

SeeSAR version 3.2 released

 

SeeSAR 3.2 can now be used in cases where there is no protein. For example if for the analysis of a ligand-based virtual screen

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Release Notes 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.
Comments

Workshop on Resources for Computational Drug Discovery

 

I just thought I'd mention this upcoming workshop, as ever there is a top class line up.

EMBL-EBI/Wellcome Trust Workshop on Resources for Computational Drug Discovery 2-6 November 2015 Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

https://registration.hinxton.wellcome.ac.uk/display_info.asp?id=510

The draft agenda is here

Comments

SeeSAR Updated

 

SeeSAR has been updated to version 3.1, the release notes highlight two significant new features.

SeeSAR is a software tool for interactive, visual compound prioritization as well as compound evolution.

  • 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.

NOTE! SeeSAR project files from older versions are incompatible and cannot be loaded. By default SeeSAR puts a new version in a separate location. The recommendation is to export your data from the old project file with the old version and import it into the latest SeeSAR. This is a one-time effort, which allows you to benefit from the features of the most up-to-date version.

Comments

Cresset update Torch and Forge

 

The update of Forge, a computational chemistry workbench for ligand-based design, includes over 170 new or improved features. Of particular note is Activity Atlas a new component enables you to summarize the SAR for a series into a visual 3D model that can be used to aid new molecule design. Forge V10.4 can now connect to an external web service, through a REST interface, to import external properties and data computed or retrieved by such web services as additional columns in the Molecules Table.

The latest version of Torch now includes Multi-parameter Optimization (MPO) options including condensing many activity and physicochemical properties into a single score representing the fit to the project profile, this has been coupled to an improved radial plot visualisation and tile display.

Comments

A Review of Medicinal Chemistry Toolkit

 

The Medicinal Chemistry Toolkit is one of the best examples yet to show how mobile devices are making an impact in science. It is becoming the "swiss army knife" for medicinal chemists with an increasing calculators that are critical for drug design. To be honest I think a lot of biologists will find it useful as well.

mctoolkit

You can read the full review here.

Comments

SeeSAR 3.0

 

BioSolveIT has just announced the release of SeeSAR 3.0.

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.

There is a review of an earlier version of SeeSAR here

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MOE updated

 

MOE2014.0901 Update is now available. MOE is a fully integrated molecular modelling and drug discovery software package.

MOE 2014.0901 updates:

Enhancements:

Protein Builder

  • Option for AMBER residue name
  • Append/prepend multiple residue sequence specified by single-letter names Builder:
  • Added H’s inherit color if there is a consistent coloring in the residue

sddesc: New -smi:p option causes field headers to be written to the output ASCII file

Bug Fixes:

  • MOESVLRUNPATH now properly honored
  • Combinatorial Builder now honors different attachment point locations on the same R-group
  • Database Save As one entry per file mode now properly generates unique filenames
  • Dock Template Forcing batch file now correctly generated
  • Saved views in .moe files now properly restored
  • Auto-save when Database Viewer display attributes are changed can now be disabled to prevent changes to the database file modification date when only the display is changed and not the database content
  • SVL function Deprotonate now works properly
  • Various MOE Project and Project Database Update bugs
  • Various minor bug fixes

There are reviews of MOE available here

Moe:- Molecular modeling
Moe Update (Jan 2009):- Molecular modeling
Review of MOE (2009.10 release):- Molecular modeling
Moe Update (December 2010.10 release):- Molecular modeling
Moe Update (December 2011 release):- Molecular modeling
Moe Update (December 2012 release):- Molecular modeling

Comments

SeeSAR Updated

 

SeeSAR it is an interactive tool for designing/improving ligands for drug discovery from BioSolve-it, that has been recently updated. Looking through the updates it is clear they have been very receptive to user feedback.

  • Solution filter, Finding interesting solutions in larger sets of compounds has 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 subset. 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, You can now join 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).
  • 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, SeeSAR now comes with 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.

There is a review of an earlier version of SeeSAR here, and a tutorial showing how to incorporate SeeSAR into a KNIME workflow.

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MedChem Wizard KNIME workflow

 

The MedChemWizard is a KNIME workflow designed to assist medicinal chemists with idea generation, ligand design and lead optimization using a number of common functional group transformations and medchem rules-of-thumb, this tutorial provided by Dr. Alastair Donald gives a detailed description of it's use.

mcwizard

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SeeSAR Updated to 2.0

 

SeeSAR has been updated to version 2.0. SeeSAR is a really interesting tool for ligand design, it enables users to explore lingered interactions in a real-time manner. There is a review of SeeSAR here. BioSolveIT have taken a strategic decision to provide rapid and regular incremental updates which means it is always worth checking to get the latest version. However this looks to be a rather more significant update.

seesarjan2015

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 may have an effect on the computed scores. If you rely on the scores resulting from a scecific version of the tool, we recommend 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 toolbox (located in the lower right corner).

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SeeSAR Updated

 

a href="http://www.biosolveit.de/SeeSAR/">SeeSAR version 1.6 has been released. It covers:

The ability to change the charge of an Atom (+/-) and to protect such change against ProToss (this is the automated protonation/tautomerism to optimize the overall H-bonding network) overwrite

Improved table: pM affinity, in/exclude multiple columns, the pose-specific context-menu, quick-find molecules including a 2D popup rendering, this can be very useful when trying to work out the structure from a 3D conformation.

seesar2d

There is a review of an early version of the software here

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VIDA v4.3.0 released

 

OpenEye have announced the release of VIDA v4.3. This is a major update with many new features and enhancements, including improvements to depiction, 2D alignment, list manager manipulation, surface selection and display, default colouring schemes, both visual and list-driven atom subset selection, cluster viewing, colouring by SD property and extension management.

One feature I’m sure will be very popular is the new advanced depiction options, including atom property maps from the Grapheme TK, substructure highlighting, and 2D structure alignment, are available for depiction in the 2D window and spreadsheet

2Ddisplay

Support for Mac OS X 10.8 and 10.9 was added
Mac OS X 10.6 is no longer supported


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POSIT updated

 

OpenEye ihave announce the release of POSIT v3.1, the component of the OEDocking suite devoted to pose prediction.

This update includes:

  • The HYBRID and FRED algorithms have been incorporated into POSIT, the appropriate method is determined by analyzing the ligand to pose against the input receptors.
  • Multiprocessing has been enabled through the use of MPI, to speed calculations.
  • POSIT now supports a list of receptors files or .lst file as input. This overcomes command-line limitations for the number of receptors that can be used simultaneously.
  • Added a MEDIOCRE result rating for results between 33% and 50% probability.
  • Command line parameters have been simplified and updated to be compatible with the OEDocking Suite of tools.

POSIT is designed for the posing problem in lead optimization, i.e. how best to leverage project information from previous protein-ligand structures to predict the pose of a new ligand. It does this by assessing the similarity of the new ligand to known bound structures. Performance degrades as similarity decreases and so at some point it is worth searching more exhaustively.



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SeeSAR updated

 

SeeSAR 1.5 has been released. SeeSAR it is intended as an interactive tool for designing/improving ligands for drug discovery.

The latest release covers two major topics: 1. A series of features that make the editing more swift and easier. To this end they introduced hot-keys, context menus and drawing a bond by drag&drop. 2. Often times people use SeeSAR for visual inspection e.g. after docking. Now normally you'll have multiple poses per compound. For a better overview the Table now allows you to collapse all poses to just one line per compound.

cihhbjhj

Furthermore you can set a bookmark to indicate what you like and export only the ones on the wish list.

There is a review of SeeSAR here.

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CheS-Mapper 2.2 released

 

CheS-Mapper has been updated, CheS-Mapper (Chemical Space Mapper) is a 3D-viewer for chemical datasets with small compounds.

The tool can be used to analyze the relationship between the structure of chemical compounds, their physico-chemical properties, and biological or toxic effects. CheS-Mapper embedds a dataset into 3D space, such that compounds that have similar feature values are close to each other. It can compute a range of descriptors and supports clustering and 3D alignment.

There is a review of Ches-Mapper here

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Sentira Review

 

Sentira is a new chemical data visualisation tool from Optibrium. The focus is on ease of use data visualisation and as such is probably targeted at the bench scientist rather than a specialist computational scientist. It supports a selection of plotting and SAR tools.

I’ve written a review of my first impressions.

There is also a list of data visualisation applications here.

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Asteris Updated

 

Asteris has been updated. Asteris is an iOS app that arose from a collaboration between Optibrium and Integrated Chemistry Design that allows medicinal chemists to design new molecules on their iPad and then calculate a range of physiochemical and ADME properties.

What's New in Version 1.0.2 Add sulfoxide support, using either double bond, or separated charges, Add multiple ring creation with one gesture if atoms are selected. Permit scaling with selected atoms and bonds. Add wavy bonds if Single bond tapped a second time. Add Presentation Mode.

There is a review of version one here

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SeeSAR Update

 

I recently wrote a review of SeeSAR and one of my comments was:-

Unfortunately there is no 2D display of ligands in the ligand list so sometimes it can be difficult to keep track of modifications.

Well, in keeping with the “fast and agile” release plan a update is now available that includes a 2D display.

2Dimage

More information

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Wiley acquired SimBioSys

 

An interesting news snippet.

Wiley acquired SimBioSys, a scientific software provider of tools used in the drug discovery process. Chemists use these tools, including the ARChem - Route Designer, to perform organic synthesis (designing synthetic routes for target molecules). ARChem’s organic chemistry system is derived from databases such as Wiley’s ChemInform Reaction Library (CIRX). The Canada-based company is privately held, and terms of its agreement with Wiley were not disclosed.

“By combining our traditional published content and databases with machine learning algorithms, we can support chemists in innovative research as they advance world knowledge” while using Wiley Science Solutions, says Steve Miron, Wiley’s SVP of global research.

I can see that logic behind acquiring ARChem since it allows them to better leverage their reaction databases, but I wonder what this means for some of the other Symbiosis tools in particular things like eHits?

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A review of SeeSAR

 

SeeSAR is an interesting new product from BioSolve-it, it is intended as an interactive tool for designing/improving ligands for drug discovery. I’ve written a brief review that you can read here.

seesar4

This is a really interesting application, it seems a little rough around the edges but the developers have released it early are very keen to get feedback. I found them very responsive and enthusiastic about getting the views of users involved in how the application evolves. I would certainly encourage people to download it and use the free trial period to give it a go, and provide them with feedback.

There are more software reviews here.

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Scripting Vortex 20

 

Vortex has a limited capacity to render HTML, it is however a very limited ability so there is no support for javascript or CSS but you can introduce a number of useful extra features.

Im the latest tutorial you can find out how to use this to add images, plots and graphs to the molecular worksheet.

Scripting Vortex 20:-Adding images to Vortex

radarplots

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Scripting Vortex 19 Updated

 

This is another Vortex script, this one is used to implement a central nervous system penetration (CNS) algorithm described in the literature.

It is clear from many publications that a number of physicochemical properties influence central nervous system (CNS) penetration and it is often possible to play off one property against another in an effort to improve CNS penetration. An interesting paper from Wagner et al Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties describes an algorithm to score compounds with respect to CNS penetration.

The CNS MPO score was built based on six fundamental physicochemical properties: ClogP, ClogD, MW, TPSA, HBD, and pKa each weighted from 0 to 1.0

Update

One of the popular features in Vortex is to colour code columns, this is done automatically but sometimes you want to customise the colouring. For example in one set of values smaller values might be better, in another columns (perhaps an off-target activity) larger numbers might be better. Chatting to Sune Askjær, the author of the Unichem Script, it seemed that this might be a nice addition to this script.

The updated script is here.

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Scripting Vortex 19

 

This is another Vortex script, this one is used to implement a central nervous system penetration (CNS) algorithm described in the literature.

It is clear from many publications that a number of physicochemical properties influence central nervous system (CNS) penetration and it is often possible to play off one property against another in an effort to improve CNS penetration. An interesting paper from Wagner et al Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties describes an algorithm to score compounds with respect to CNS penetration.

The CNS MPO score was built based on six fundamental physicochemical properties: ClogP, ClogD, MW, TPSA, HBD, and pKa each weighted from 0 to 1.0 full details of the script are here.

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Asteris, molecular design on the iPad

I’ve just finished a brief review of Asteris is a new iOS app that arose from a collaboration between Optibrium and Integrated Chemistry Design that allows medicinal chemists to design new molecules on their iPad and then calculate a range of physiochemical and ADME properties.

The complete review is here, and there is a full listing of reviews here.

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Asteris

We are starting to see companies exploit the client server model in bringing ever more sophisticated scientific applications to the iPad.

Asteris is a joint development from Optibrium the creators of StarDrop and Integrated Chemistry Design who created Chirys Draw. Asteris uses Chirys Draw’s touch interface to design novel molecules and then uses StarDrop’s predictive modeling power, guided by the Glowing Molecule™ visualization, instant feedback dramatically reduces the time it takes you to identify high quality compound designs. Using Asteris you can calculate a range of simple “core properties”, and ADME properties, including solubility, hERG inhibition and CNS penetration, using rigorously validated models from the StarDrop platform.

  • CORE PROPERTIES
  • Molecular Weight
  • Number of rotatable bonds
  • Flexibility
  • Number of hydrogen bond donors
  • Number of hydrogen bond acceptors
  • Topological polar surface area.
  • logP
  • STARDROP ADME PROPERTIES
  • logS
  • logS7.4
  • logD
  • 2C9 pKi
  • hERGpIC50
  • BBB log([brain]:[blood])
  • BBB category
  • HIA category
  • P-gp category
  • 2D6 affinity category
  • PPB90 category
asteris

All of the predictions are calculated using StarDrop ’s ADME QSAR module. You will need to be connected to the internet to perform these calculations using the secure Asteris cloud server.Alternatively, you can run the calculations on your own server with the “Enterprise” edition.

All communications with the server uses industry-standard SSL encryption. No compound structures or data are stored on the server. Calculate "core properties" for an unlimited number of molecules for free. Calculate ADME properties for 20 new compounds each month, free of charge. Additional ADME property calculations can be purchased via an in-app purchase.

There are demo videos on the support site.

Comments

pKa Prospector

 

OpenEye have just announced the release of pKa Prospector v1.0 a database of high quality experimental pKa determinations. The ionisation state of a drug molecule can have profound effects on affinity, dissolution, absorption, distribution, metabolism and off-target activity. The ability to predict pKa is often compromised by the lack of relevant experimental data, pKa Prospector is intended to address that issue.

The built-in experimental pKa database was compiled by Tony Slater of pKaData Limited from a collection of IUPAC sources. Each measurement has been individually verified, curated, and assigned a metric of quality. There are more than 30,000 experiments across 12,000 molecules represented. The database is particularly relevant for medicinal chemistry due to the strong preponderance of room temperature aqueous measurements, the many molecules with multiple experimental records, and the presence of over three hundred different heterocycles.

It is also possible to add additional experimental results and have them integrated into the application thus expanding the chemical space covered. The search uses rooted maximum common substructure (MCS) with "electronically-aware" scoring, alternatively it can be searched by similarity or substructure. Ionizable groups are automatically identified and highlighted.

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SYBYL-X 2.1.1 released

 

SYBYL-X 2.1.1 is now available, the focus of this release is to extend the capabilities available via the standalone PYTHON interface to 3D-QSAR, which was introduced in SYBYL-X 2.1 earlier this year. The PYTHON API allows 3D-QSAR models (CoMFA, CoMSIA, and Topomer CoMFA) to be created and used for predictions outside of SYBYL-X.

  1. Hologram QSAR (HQSAR) is a now available via Python.  HQSAR has been successfully applied to generate predictive global QSAR models for on- and off-target effects and models for important ADME related properties; the HQSAR method employs 2D-substructural counts as descriptors.

  2. Similarity computations and similarity searches (UNITY 2D fingerprints) are now accessible via Python to support various workflows, such as lead expansion, lead hopping, and cluster analysis.

Comments

Turning up the heat with Torch and Forge

 

Anyone involved in a drug discovery programme will be aware of the challenge presented by trying to visualise and explore structure-activity relationships (SAR), in particular visualising questions like :-

“What is the largest change that can be made whilst maintaining activity?”

Activity Miner from Cresset is a new tool designed to rapidly interrogate and decipher SAR in both Torch and Forge. Activity Miner is intended to help identify key elements of the SAR by starting from a set of aligned molecules and then automatically comparing them to each other.

Activity Miner1

More details are here

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VHELIBS, a validation helper for ligands and binding sites

The Validation HElper for LIgands and Binding Sites (VHELIBS) is software that aims to ease the validation of binding site and ligand coordinates for non-crystallographers. It is written in java and can be downloaded from github here. I have not tested it extensivey but on my cursory look it seems to work fine under Mac OS X, provided you have installed java.

Using a convenient graphical user interface, it allows one to check how ligand and binding site coordinates fit to the electron density map. VHELIBS can use models from either the PDB or the PDB_REDO databank of re-refined and re-built crystallographic models. The user can specify threshold values for a series of properties related to the fit of coordinates to electron density (Real Space R, Real Space Correlation Coefficient and average occupancy are used by default). VHELIBS will automatically classify residues and ligands as Good, Dubious or Bad based on the specified limits. The user is also able to visually check the quality of the fit of residues and ligands to the electron density map and reclassify them if needed.

To start the application simply double-click on the icon, and then enter a PDB code (or you can load a list from a file) the analysis takes a few mins so if you are planning to examine a list of structures you may want to set it running overnight. The results can then be examined in the viewer which is uses JMOL.

vhelibs

It all seems pretty intuitive. In the view above the ligand atoms are purple and the associated electron density red, the protein atoms are white and a dubious area of associated electron density is shown in yellow.

You can read more details here Journal of Cheminformatics 2013, 5:36 doi.



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BlazeGPU

I was at the Cresset UGM last week and had a chance to hear more about BlazeGPU. The original CPU application Blaze uses the shape and electrostatic character of known ligands to rapidly search large chemical collections for molecules with similar properties. The latest version BlazeGPU runs at 40 times the speed of the CPU version of Blaze but loses nothing in accuracy. At a fraction of the hardware cost, BlazeGPU delivers the same effective, ligand based virtual screening as Blaze, based on the shape and electrostatic nature of molecules.

BlazeGPU is written in OpenCL and OpenCL libraries are available from NVidia and AMD for their graphics cards, but also from Intel for the CPU and for their new Xeon Phi coprocessor cards. BlazeGPU is currently designed only to run on the GPU - for CPU-only clusters the original code is just as fast, and on a machine with a reasonably fast GPU or two the CPU tends to run flat out just feeding data to the graphics card, so there's not that much gain running on the CPU as well as the GPU.

Currently the conformer generation still runs on the CPU, but they are looking at the possibility of porting that to OpenCL as well in the future.

The relative performance is shown in the plot below, it is worth noting that these are relatively inexpensive graphics cards that you can pick up on Amazon or ebay for a few hundred pounds. Also note for a $2.10/hour GPU instance on AmazonEC2 you can process 2m conformations.

BlazeGPU

There are more examples of GPU science here.



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Molegro Virtual Docker Update

An update to the Molegro Virtual Docker has been announced. It includes new data analysis tools that are now available directly from within Molegro Virtual Docker. Some of the new features include:

  • New and powerful regression features: Support Vector Machine regression and Partial Least Squares
  • Classification using either K-Nearest Neighbors or Support Vector Machine classification
  • Automated fine-tuning of regression and classification model parameters
  • Spring-Mass Maps for visualization of high-dimensional data
  • Clustering of data sets and subset selection
  • Principal Component Analysis
  • Outlier Detection



Comments

OEDocking updated

OpenEye has announced the release of OEDocking v3.0.1. This is a bug fix release to the FRED, HYBRID, and POSIT programs. Of note, the report generated by both FRED and HYBRID has been significantly improved with this release

CHANGES

  • The program dockreport has been renamed to DOCKINGREPORT

NEW FEATURES AND IMPROVEMENTS

  • The formatting of the DOCKING_REPORT has been significantly improved and now includes:
  • Added a protein interaction fingerprint
  • XLogP
  • Polar Surface Area (PSA)
  • Improved the geometry detection for hydrogen bond protein constraints in FRED and HYBRID. These constraints should now be tighter.

BUG FIXES

  • Stereo isomer detection in POSIT was not handling bridgeheads properly, this caused some non-stereo molecules to be identified as such.
  • Fixed a bug in FRED and HYBRID where clash detection between hydrogen bonding groups was occasionally too strict.



Comments

StarDrop 5.3 is now available

Optibrium have just announced that StarDrop 5.3 is now available, including many new features, the highlights include:

  • Virtual Library Enumeration – The Nova plug-in module for StarDrop now has the added ability to quickly and easily enumerate a virtual library based on a template scaffold that you define with substitution points and variable fragments. You can sketch the groups to substitute at each point, select them from a user-defined or centrally administered library, or take them from a decomposition of another series using the R-group analysis tool in StarDrop
  • Data visualisation - now allows you to apply interactive filters to your graphs and plots to quickly focus on the most interesting compounds. StarDrop now also supports the analysis of dates allowing you to explore variations of properties or scores with time
  • Clustering - this new tool enables you to easily identify groups of similar compounds within a data set, based on either their structural similarity or properties
  • Dataset Filtering - this helps you to remove compounds from a data set with unwanted sub-structures or property values. You can define any number of criteria with which to filter a data set
  • Duplicate Removal - when combining compound data from multiple sources it’s common to end up with multiple copies of the same compound in a single data set. The duplicate removal tool makes it easy to find these and choose the entries that you want to keep.
  • ADME QSAR – new model for predicting log([Brain]:[Blood]) (the old model remains available for consistency with previously calculated results)



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SMARTCyp 2.4 released

The new SMARTCyp version 2.4 includes solvent accessible surface area (SASA) in the scoring function. SASA is computed using the 2DSASA algorithm from 2D coordinates.

smartcyp

  A paper describing the new models and their predictive accuracy on nine CYP isoforms is available in Molecular Pharmaceutics DOI



Comments

SMARTCyp Updated

SMARTCyp 2.3 has been released with some additional improvements including: Improved energies for N-oxidations Empirical correction for unlikely N-oxidations of tertiary alkylamines A filtering functionality for excluding compounds with very low activation barriers to CYP-mediated oxidations A smiles string can now be input directly on the command line using the -smiles flag.   Available as usual at http://www.farma.ku.dk/smartcyp   The science behind the improved N-oxidations and the empirical correction has also been published in a paper in Angewandte Chemie: DOI  

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New tools from COSMOLOGIC

Two brand new tools from COSMOlogic which might be of greater interest for all those working in drug design:

1) COSMOsim3D Based on an idea of Michael Thormann (Origenis) we have implemented COSMOsim3D as a very efficient method for alignment and 3D similarity using local sigma profiles, i.e. local histograms of the COSMO sigma surface on a 3D grid. By that molecules get aligned in a way that maximum similarity of the sigma surfaces is achieved. In a paper which has just got online in JCIM (see http://pubs.acs.org/doi/abs/10.1021/ci300205p) we demonstrate the extraordinary performance of this method for bioisoster search and drug activity class enrichment.

2) COSMOsar3D According to COSMO-RS theory, which is widely validated in fluid phase thermodynamics, the final grid of local sigma profiles produced at the end of a COSMOsim3D alignment of ligands should represent a complete set of descriptors for molecular interactions. Furthermore it can be shown that with these descriptors the free energy of binding of a ligand in a receptor should be a linear function of the descriptors, and thus be optimally suited for the PLS analysis usally applied in molecular field analysis. Therefore we implemented the COSMOsar3D method a new variant of the traditional comparative field analysis, know as CoMFA. And indeed, testing this idea on the Sutherland data set we could show that it outperforms the seven reported 3D-QSAR methods tested therein not only with respect to prediction accuracy, but also with respect to robustness with respect to grid position, grid size, and small misalignments of the ligands. (see http://pubs.acs.org/doi/abs/10.1021/ci30 0231t)

Everybody who likes to test these two methods on his datasets is invited to do this based on a free evaluation license. You can use the tools either stand alone, or integrated in the Open3DQSAR software (http://open3dqsar.sourceforge.net/)

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Cresset Product Update

I was at the Cresset Science Meeting last week and heard about the plans to update their comprehensive suit of drug discovery and design computational tools.

Together with an interesting updates to the tools the suite has undergone something of a makeover, all of the software tools have be renamed using a “Fire” theme and refocussed to specific users needs rather than the software capabilities. The renaming will not be complete until September so in the interim the links on some of the download pages still point to the originally named application.

TorchV10lite is a free 3D molecule viewing, editing and drawing application that shows your molecules in 3D overlaid with field patterns generated using their proprietary field technology together with 2D structure and physicochemical properties. It is the replacement of FieldView.

TorchV10 is a powerful design and 3D SAR tool for medicinal chemists. It is used to take leaps in structural design by identifying compounds with similar fields but different 2D chemical structures while maintaining or improving biological activity. It is the replacement for FieldAlign and due for release very soon.

SparkV10 is a powerful way of generating novel and diverse structures for your project.  sparkV10 uses Cresset’s field technology to find biologically equivalent replacements for key moieties in your molecule, enabling you to find new structures in new chemical space. You can then use calculated physiochemical properties to filter and select the best designs. sparkV10 is the exciting replacement for FieldStere and due for release very soon.

The three applications above look to be intended for use by Medicinal Chemists whilst the remaining two applications are perhaps better suited to those more experienced in computational chemistry.

ForgeV10 takes advantage of Cresset’s patented ligand comparison method to align, score and compare molecules from a biological viewpoint, using the shape and electrostatic character of your molecules to create qualitative and quantitative 3D models of activity. forgeV10 combines FieldAlign and FieldTemplater in a single application,

BlazeV10 uses the shape and electrostatic character of known ligands to rapidly search large chemical collections for molecules with similar shape and electrostatic properties. It is installed and runs on a Linux cluster but is operated through a web-browser, enabling access from any platform and multiple locations.

Many molecular visualisation/modelling tools seem to assume the charge associated with an atom sits as a point at the centre of the nucleus, whilst this makes the computation easy it does not really reflect what the electrostatic surface really “looks like”. Cresset has pioneered the use of field point descriptors to give a more accurate description of the charge around an atom and to enable better comparisons and visualisation. This has been shown to be particularly important when trying to understand some molecular interactions such as Aryl-Aryl interactions or creating bioisosteric replacements.

HeteroFields

Cresset now have an impressive suite of tools for drug discovery and I hope to review them in due course.

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