Blaze V10.2 released

We are delighted to announce the release of Blaze V10.2. This version of our unique virtual screening software contains major enhancements to the workflow that improves results and reduces the search time, a new REST interface to enable enhanced integration and an improved security system. We have also released a new fully functional Blaze Cloud demo server.

Blaze search cascade

Blaze Search cascade

FieldPrint

FieldClique

FieldSimplex

We’ve taken a fresh look at the workflow of a typical Blaze experiment. We use a search cascade (right) in Blaze to enable us to process large databases of compounds (typically up to 10 million) in a time efficient but detailed manner. The cascade uses field finger prints (FieldPrints) to do a rapid search across the entire database. However, we know that methods derived from distilling the field down to a simple vector representation are not as accurate as performing full alignments and therefore developed a quick alignment method ‘FieldClique’ to do exactly this. In FieldClique we perform a rapid alignment and single point score to get a good estimate of the final optimized alignment score. This method is significantly more accurate than FieldPrint but still less accurate than the fully optimized alignment score which we get from a FieldSimplex routine. The accuracy of these 3 different methods is used to cascade the number of compounds through the virtual screening experiment. All compounds receive a FieldPrint score, around 30-50% receive a FieldClique score and around 5% receive the most accurate FieldSimplex score.

Greater throughput of molecules

We have been looking at improving the performance of the screening cascade for some time with a desire to fully align more molecules. For customers with GPU clusters this is less of a problem as the throughput of the GPU code is so good. In this release of Blaze we have introduced a new algorithm for the FieldClique method that enables a much greater throughput of molecules but at the cost of some accuracy. The new algorithm is around four times faster than the previous one, enabling 4 times as many molecules to be processed in the same time. In testing we have found that the loss of accuracy is more than compensated for by the ability to process more molecules in a full 3D alignment method and by subsequent FieldSimplex refinements. We recommend that whenever computing resources are available you should be refining greater than 50% of the FieldPrint results using the new fast FieldClique routine.

Number of compounds FieldPrint FieldClique FieldSimplex Typical Time using 250 CPU cluster
Normal Mode 4 500 000 1 500 000 150 000 4 hours
Fast Mode 4 500 000 3 000 000 150 000 2.3 hours

 

Interact with Blaze through many different environments

This version of Blaze comes with a new RESTful web service that enables you to interact with Blaze through many different environments. The fully documented methods provide access to all of Blaze’s features including searching, collection management and result retrieval. This highly requested feature provides easy integration with workflow solutions such as KNIME and Pipeline Pilot and enables Blaze integration with custom software solutions as well as enhancing the integration with future versions of Cresset’s desktop applications such as Forge.

A Blaze search using KNIME

A KNIME workflow for searching Blaze

Enhanced security features

One of the key requests from our customers has been to simplify and unify the excellent security features of Blaze with their corporate policies. In this release we have achieved this by adding support for the apache web server authentication modules. This new integration enables you to roll Blaze out to a wider audience without the previously required management of user names and passwords. This will prove especially useful as we roll out enhancements to the desktop products that enable full control of Blaze from within those applications.

Free demo server

The new features above have enabled us to enhance our Blaze SaaS offering to include access from KNIME and to offer a demo server to the community at large. The demo server is fully functional – you can search a small collection of compounds using the standard search cascades, manage compound collections etc. Blaze is remarkable easy to use but should you require advice then the software comes with a full manual and context sensitive help on every page. You are welcome to use it from a web browser or using the REST interface. Register for your username and password at the Blaze demo signup page.

Spark V10.2 released

We are delighted to announce the release of a new version of Spark, our innovative tool for finding biologically equivalent replacements for key moieties in your molecule. This release contains many new features and improvements to the user interface along with new databases of bioisosteric fragments and hence is highly recommended for all users. Two key focuses for this version have been to improve the link between suggested bioisosteres and the available synthetic and property space of your project, and to make ranking Spark’s suggestions on multiple physicochemical properties easier and more intuitive.

Spark Radial Plot

 


The new radial plots summarize the properties of Spark result molecules in an instantly readable and interpretable way. These totally customizable and sortable additions to the molecule table enable the rapid visual profiling of new bioisosteres against personal, project or corporate physicochemical properties. Setting up the plots is easy – just pick the property to be added to the plot from a drop down list. The settings for ‘good’ and ‘acceptable’ values are easily customizable so that you can create a corporate or project based profile that can be used in every Spark experiment. Sorting on the radial plot column causes the result molecules with the best overall properties to rise to the top of the table, reducing the time taken to choose the best possible synthetic direction for your project.

A field difference in Spark

The areas of more positive (red) and more negative (blue) field are highlighted for a result molecule (right) compared with the starting compound (left).

 


The new ‘field difference’ display mode enables greater understanding of the effect of a specific change on the electrostatic and shape properties of your molecule. In this mode the regions of change in field of the result molecule are highlighted next to the starting molecule. Thus regions that become more positive or negative are easily spotted giving greater understanding of the differing shape and electrostatic characteristics of a change.

New in this version of Spark are databases of fragments derived from chemical reagents and building blocks. These new databases enable the use of Spark to scan the immediately available chemical space for the best possible move. The databases come from the processing of sets of commercially-available reagents with simple, chemically intuitive rules for generation of R groups. Over 20 different reagent databases are provided by Cresset using the current rules,which can be easily modified to suit your preferences. If you think we’ve missed something then let us know and we can add it to the list in minutes.

Customers with a database generator license can use our rules to process their own available reagents, giving rapid suggestions for the next set of compounds to be made using the reagents currently in your lab. Often these suggestions will warrant further investigation in Torch or Forge and so we have enhanced the link to these applications from Spark with a new “Send to” menu entry that transfers results to the chosen application.

Lastly we’ve introduced the option to create databases by fragmenting molecules that exist in a predefined conformation, such as those from small molecule crystal structures. We will be investigating the delivery of Cresset calculated databases from these sources in the next few months. However, customers with the database generator can use this mode immediately on their own or public crystal structures to further enhance their sources of bioisosteres.

This release of Spark is a significant advance: existing users will see great benefits from updating, while if you’re not already a Spark user contact us for a free evaluation to see what you’re missing out on!

SparkV10.2

Forge V10.2 released

Cresset are delighted to announce the release of a new version of Forge, the powerful computational suite to understand SAR and design. This version comes with a major new module ‘Activity Miner‘ that enables the understanding and navigation of structure activity relationships through the use of 2D and 3D activity cliffs. However, we have also introduced significant enhancements to the main application in this version with the introduction of:

  • csv file reading of molecules and data
  • a fullscreen view of the 3D window
  • the option to convert specific protein-ligand interactions into field points
  • and many more improvements to the look and feel of the application.

Activity Miner is designed to give you rapid access to the important points in the structure activity relationships of your projects. It uses the concept of ‘activity cliffs’ or ‘disparity’ to identify where a small change in the molecule has caused a large change in the measured activity. Uniquely, Activity Miner works using multiple metrics for deciding if a change is significant or not. Activity Miner is an additional module to both Forge and Torch and is included with every new or existing Forge license. See the Activity Miner page for more information or see it in action in these short videos.

Activity Miner's Activity View

The user interface has had a number of significant developments, such as:

  • addition of csv reading of molecules (also included in the equivalent version of Torch)
  • drag and drop file reading in windows
  • fullscreen display of the 3D window
  • toggle of the visible protein atoms to just those around the reference molecules.

In this version we have also introduced the ability to encode and constrain a specific protein-ligand interaction in your ligand based design. Simply right click on a protein atom that is involved in an important interaction with the protein and it will be converted to an appropriate electrostatic field point on the reference molecule. You have always been able to constrain the similarity algorithm to make sure certain field points are matched, but combining these constraints with the new functionality makes it possible to ensure that a specific interaction is present in every aligned ligand. Naturally you will want to use this feature with our virtual screening system Blaze. Forge V10.2 improves the integration between the two applications such that you can upload a ligand-protein complex directly to your own Blaze server from the right click menu.

We are confident that you will enjoy all the new features in this release. You can see a full list of improvements in the release notes or take a free evaluation of Forge with the Activity Miner module here.

Torch V10.2 released

Cresset are delighted to announce the release of a new version of Torch, the intuitive molecule design suite for medicinal chemists. This version comes with many new features and significant interface enhancements.  It also includes the new Activity Miner module for SAR interpretation and understanding.

Activity Miner

Activity Miner is designed to give you rapid access to the important points in the structure activity relationships of your projects. It uses the concept of ‘activity cliffs’ or ‘disparity’ to identify where a small change in the molecule has caused a large change in the measured activity. Uniquely, Activity Miner works using multiple metrics for deciding if a change is significant or not. See the Activity Miner page for more information or see it in action in these short videos.

Activity Miner's Activity View

Torch Interface Improvements

The main Torch interface has received significant improvements, such as:

  • the new Fullscreen mode
  • the inclusion of additional columns into the results table, including Ligand Efficiency (LE) and Lipophilic Ligand Efficiency (LLE) data for every molecule
  • an option to import molecules from or update the data for molecules from csv files.

The new Fullscreen mode gives the option to display the 3D window across the whole of one monitor. We use it to discuss molecule designs or protein-ligand interactions in meetings but you could equally use it for creating stunning pictures for papers or for browsing the results of an alignment experiment. You can now ‘rock’ or ‘spin’ the 3D display at the same time for sensational full screen presentations. This short video shows it in action:

In this new version of Torch any activity data that is associated with your molecules is automatically detected and used to calculate activity based properties such as the ligand efficiency and the lipophilic ligand efficiency. You have always had the ability to filter the molecules in the table but with these new properties it is easier than ever to focus your thoughts on the compounds with the best possible match of physical and activity criteria.

Other improvements to the results table include a ‘notes’ field associated with every molecule so that you can record your thinking when you are designing a new compound. Simply type the notes into the molecule editor and they will be automatically transferred to the main table when you save the molecule.

Creating Molecule Notes in Torch

The ways to load molecules into Torch continue to expand and improve. In previous versions we introduced reading molecules from smiles and the ability to download and process pdb files. In this version you have support for reading both molecules and data from csv files, making the loading and updating of molecule associated data easier than ever. Simply open the csv file, choose to load molecules or data and specify which column contains the molecule smiles or the matching field. See it in action in this short video:

Download a FREE Evaluation

You can try all these features with a free evaluation of Torch, or contact us to find out more.

BlazeGPU released

We are delighted to announce the release of BlazeGPU. This update to Blaze is available to all customers at no extra charge and includes all of the infrastructure needed to convert a standard blaze install to the GPU version.

Our 18 month project to convert our core algorithms to run in a GPU environment has achieved a fantastic 50 times speed up (see the graph on the BlazeGPU page). This massive increase in speed has been achieved without losing any accuracy; in fact BlazeGPU gives slightly better results than previous versions. Additionally, we have found that we get significant speed increases on consumer devices as well as high-performance accelerated devices.

BlazeGPU Speed Data
We are looking forward to using the new capabilities of BlazeGPU to investigate problems that we had not previously been able to look at. For example we have been looking at 3D molecular similarity in compound collections using our technology and are expecting to be able to increase the pace of this research with our new code.

BlazeGPU has enabled us to improve the throughput of projects using our Consulting and Software as a service offerings. We have invested in new hardware at a cost of only $2000 that effectively doubles the throughput of our 150 node Linux cluster. We are investigating the creation of a portable cluster that will be available for our clients to use on their premises. This ‘COW’ will be available to use on virtual screening campaigns by our clients shortly. Please get in touch with us to find out more.

We forward to bringing similar speed increases into our desktop applications in due course.

Modeling Halo-benzenes in XED3

There has been some debate recently over the modeling of protein-ligand interactions. Herein we show how XED3 models interactions to the halo-benzenes and to a range of other hetero-aromatics. It is interesting to contrast the MEPs for the halo-benzenese with those reported in a recent QM study.

halo-benzenes_XED3

Below is the MEPs for a range of hetero-aromatics as modelled in Forge. Interested? Try it for yourself with a free demo or get TorchLite free for 12 months.

hets_XED3

forgeV10.1 Released

A new version of Forge is available now. This version brings many new and improved features and is recommended for all users. Of particular note are:

  • the ability to apply differential weights to multiple reference molecules,
  • a new context sensitive menu on the 3D window,
  • support for viewing Blaze result files and legacy FieldView projects,
  • an improved workflow for molecule design and improved pdb download and processing.

Forge is Cresset’s computational workbench to understand SAR and design. Free evaluations are available by simply registering for a demo or contacting us for pricing and licensing options.

Weighting multiple reference molecules

Using multiple reference molecules in Forge is a good way to add extra information to your alignment and 3D-QSAR experiments. Incorporating references that bind to different parts of the active site of the protein or incorporate diverse functionality significantly improves the alignment of diverse active molecules. However, the alignment step has always assumed that the reference molecules are equally important.

In this release we have introduced the ability to make reference molecules more or less important by modifying the proportion of the score that is derived from that reference. Now the handling of multiple reference molecules becomes very flexible, giving you the option to control the weighting scheme, for example by using the maximum score against any reference or by using a weighted average of scores.

This capability will help with SAR interpretations that involve many chemotypes and also with design experiments where you are trying to build a set of interactions that exist in one series into another.

forgeV10.1 Reference Weights

A new context sensitive menu

A new context sensitive menu on the 3D window makes examining and modifying alignments simpler than ever. Right clicking on an atom gives you options to select, copy or edit the selected molecule.

When several molecules are displayed at once, this simple new capability becomes a powerful way of selecting molecules with interesting alignments, of modifying interesting compounds and of repairing mis-aligned molecules.

forgeV10 3D context menu

Enhanced molecule viewing capabilities

This release of Forge brings enhanced molecule viewing capabilities. We have taken all the capabilities of Cresset’s legacy FieldView product and added them into Forge. This gives you the ability to load, sketch and view molecules, including their field patterns, as well as to load and view Blaze results files.

Loading a Blaze result file in ForgeV10.1 is now a smooth process.  Reference, protein and database molecules are auto-recognized and displayed appropriately. To make life easier still, we’ve added a wizard entry to give rapid access to the analysis of Blaze results (see screenshot, below).

forgeV10.1 wizard

A simple protein import process

The simple protein import process that we released in torchV10 has been introduced in this release of Forge. Aimed at the rapid and simple processing of pdb files into reference ligands and protein excluded volumes, the pdb import has been an instant hit with Torch users. Using a hierarchical, sortable view of the protein enables the loading specific protein chains, removal of all or just “hot” waters molecules, and rapid identification of the bound ligand. This short Forge video shows the process.

Forge is Cresset’s computational workbench to understand SAR and design. Free evaluations are available by simply registering for a demo or contacting us for pricing and licensing options.

Rapid pdb Processing in Forge

The video below shows how a pdb file can be downloaded and rapidly processed into ligand and protein using Forge. It shows how to use the wizard interface to set up an experiment and view and export the results.

iPhone and iPad users can see the video using this link.

Is Chocolate Druggable? Using Theobromine for Desktop Virtual Screening

Dr Rae Lawrence, Cresset’s Technical Sales Director for North America, is a self confessed chocoholic.  For this blog she has spent some quality time with her favorite food, investigating the chemistry of the compounds that produce the delicious taste, desirable effects, and even the addictiveness claimed by some.  With Valentine’s Day just behind us and Easter around the corner, there’s no better time to think about this wonderful topic!

Dark chocolate has long been reputed to be a healthy dietary addition.  It is claimed to be a mood enhancer, cough suppressant, and a key nutritional supplement for cardiovascular health.

There are a few hundred pharmacologically active compounds in chocolate, including, but not limited to:

  • Theobromine and caffeine (CNS stimulants);
  • Salsolinol  – dopaminergically active, and possibly responsible for chocoholism1;
  • Anandamide  – an endogenous cannabinoid neurotransmitter;
  • Phenylethylamine – the alleged ‘love chemical’, another endogenous neutrotransmitter.

Even within this short list of components, it’s easy to see that given their CNS activity, chocolate is indeed mood-altering.

For this discussion, I will focus on theobromine, which is the component responsible for many of chocolate’s pharmacological effects and its bitter taste.  Theobromine is part of the methylxanthine class of compounds and has a similar structure to caffeine.  Pharmacologically, theobromine is a known antagonist of both Adenosine A1 and A2a receptors, as well as an inhibitor of cAMP-specific-3’,5’-cyclic phosphodiesterase 4B (PDE4B).2

This month I will use the virtual screening capabilities of forgeV10 to compare the biological properties of theobromine to a database of known pharmaceutically active compounds. For more information or a demonstration of how we compare molecules in field space, please contact sales@cresset-group.com or read our 2006 paper, which summarizes the technology and algorithms3.

Scouring the Literature and Google

When I started researching the pharmacology of chocolate, I discovered that theobromine appears in nefarious message boards4 suggesting that it can be used for a legal high when taken as an extract.  Reading a little further down the board, one user noted that theobromine itself didn’t really give the desired opiate numbing effect (considering its similarity to caffeine, no surprise there).  However, when they took kratom5 with it, the effects of kratom were more pronounced.

My interest was piqued by this, so I googled ‘theobromine opiate’ and while digging through the results, found a couple of peer-reviewed articles where it was reported that a shot of adenosine during anesthesia and surgery reduces the amount of opioid pain-killers required for post-operative recovery6.  Pharmacologically, theobromine binds to the A1 and A2a receptors, and thus, it is plausible that theobromine may have a similar, albeit, less pronounced effect – and given the anecdotal evidence provided by law-bending netizens and their search for inexpensive, legal highs, we might be on to something!

Theobromine and Adenosine, Adenine and N9-methyladeninea

Figure 1: Theobromine and Adenosine, Adenine and a N9-methyladenine.  Blue field points are negative, red field points are positive, yellow field points denote shape, and orange field points denote hydrophobicity.

Notice the lower similarity score when comparing adenosine to theobromine.  The decreased similarity is a result of the molecules’ different sizes.  When we look at the similarity scores for Adenine and the modified N9-methyladenine, the scores suggest higher similarity for the fragments.  This suggests that theobromine is likely accessing the same part of the Adenosine Receptors’ binding site as the purine piece of the natural ligand, adenosine.

Theobromine’s Anti-Tussive Properties

In a recent publication from National Heart and Lung Institute (London)7, it was demonstrated that theobromine has significant anti-tussive (cough suppressing) properties via inhibiting action potentials in the vagus nerve.  Theobromine’s activity was compared against codeine, which is the gold standard in cough suppression, and was found to be as good as codeine, and without the adverse side effects or addiction risk.  BC1036 (theobromine) is currently being developed by SEEK and Pernix Therapeutics and is has just begun Phase III trials.

Theobromine with codeine

Figure 2: Theobromine and codeine compared in field point space.  The low similarity score leads us to hypothesize that these molecules are likely to be binding to different receptors or alternate areas of the same receptor responsible for relaxation of the vagus nerve.

Desktop Virtual Screening

With the plethora of information about the pharmacology of chocolate, I thought it would be interesting to run a desktop virtual screen of theobromine against the Drug Bank’s databases8 of approved drugs using forgeV10.  Since theobromine is a fairly rigid flat molecule, we don’t need to be concerned with elucidating a binding mode.

Examination of the PDB structure9 3RFM, in which caffeine is bound in the A2a receptor, showed the binding conformation of caffeine to be flat and rigid, comparable to the theobromine conformation used as a starting point reference for the experiments outlined in this article.

Before conducting any experiments, the Drug Bank databases were visually inspected and curated (i.e., removal of counter ions, waters, etc.), leaving only the drug structure.  The structures within the approved database ranged from quite small to quite large and floppy, so in hindsight, I should have run only their small molecule database – it would have been far less stress on my poor laptop.

When aligning molecules under Normal settings within forgeV10 (or torchV10), it is important to note that the molecules are not aligned simply on structure, but on their field point patterns – it’s well reported that even when the 2D structural similarity is low, it’s possible that two compounds can have similar “personalities” (i.e., shape, hydrophobicity, and charge distribution)3.

Results

In the approved drugs database, the top hits were as expected – theobromine (0.998) and caffeine (0.942).

Theobromine with caffeine

Figure 3: Comparing Theobromine and Caffeine.

The next best scoring results were a series of PDE inhibitors that result in vasodilation and bronchodilation, and are used in treatment for asthma and COPD patients.  These are as expected, as the xanthine moiety is conserved through this set of compounds.

Theobromine and PDE inhibitors

Figure 4:  Comparing Theobromine to PDE inhibitors used for vasodilation and bronchiodilation for the treatment of asthma and COPD.

A surprising set of hits were lower scoring (0.729-0.799), but don’t share the xanthine scaffold.

Lower scoring comparisons with theobromine

Figure 5: Lower scoring comparisons for Theobromine.  The similarity scores aren’t fantastic, but they are still worth a look.

Azetazolamide is carbonic anhydrase inhibitor used as an anti-convulsant and to relieve intracranial hypertension; Pyridoxal and Pyridoxine are forms of Vitamin B6; Menadione is Vitamin K3;  Metharbital is an anti-convulsant barbiturate with similar properties to phenobarbital; Stavudine is a nucleoside analog reverse transcriptase inhibitor (NARTI) with some activity against HIV; and Oxitriptan is a chemical precursor to serontonin and melatonin, and is sold as a nutritional supplement for anti-depression and insomnia.

It is noteworthy that if we look at the rotamers of the hydroxyl groups of pyridoxal and pyridoxine, the alignment score decreases.

Could chocolate be a vitamin/anti-depressant truth-serum that helps with high blood pressure and HIV?  Seems like a snake-oil claim, like those single cures sold in the late 19th century that simultaneously cured diarrhea and constipation!

These lower scoring results are on the borderline of what I would consider worth a peek, but at the same time, it’s interesting to note that there are some similarities to theobromine – perhaps a re-profiling study is in order? (See Rob Scoffin’s recent posts for more information about teaching old drugs new tricks).

Summary

In cases presented above and examining the hits from the desktop virtual screens, it’s clear that the pharmacological activity of theobromine is both exceptional and diverse.  Being a small molecule, it’s no surprise that this fragment can access binding sites in a variety of targets to achieve medicinal effects!

To answer the question of whether chocolate is druggable, given the success of the theobromine anti-tussive drug that is currently in Phase III trials, I’d have to say “yes”.  That being said, I don’t think we have enough evidence here to support confiscating Cadbury Easter eggs from your children next month with the explanation that they contain “drugs”…

Until next month,

Rae

References and Citations

  1. J. Ethnopharmacol., 2000, 73, 1530159; Physiol. Behav., 2011, 104 (5), 816-822.
  2. http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=37T
  3. J. Chem. Inf. Model., 2006, 46(2), 665-676.
  4. www.legalhighsforum.com/archive/index.php/t-2758.html
  5. Kratom is a traditional Thai medicine used to treat chronic pain and opioid dependence. It is not currently regulated in the USA or Europe.
  6. Eur. J. Pharmacology, 1998, 347 (1), 1-11.; Anesthesia & Analgesia, 2007, 105 (2), 489-494.; Korean J. Pain, 2011, 24 (1), 7-12.
  7. The FASEB Journal, 2005, 19 (3), 231-233.
  8. DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, Neveu V, Djoumbou Y, Eisner R, Guo AC, Wishart DS. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. 
PMID: 21059682;  DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. 
PMID: 18048412;  DrugBank: a comprehensive resource for in silico drug discovery and exploration. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72. 
PMID: 16381955.
  9. http://www.rcsb.org/pdb/explore/explore.do?structureId=3rfm

Additional Notes

Safety First – Theobromine is extremely toxic to dogs (LD50 – 300 mg/kg). Please be careful to keep your chocolate treats (especially dark chocolate) out of reach of pets.  Chocolate + Dog = Expensive visit to the vet

Adenosine A1 Antagonism

The Adenosine A1 receptor is a GCPR receptor for which adenosine is the endogenous ligand, and has been found to be involved in sleep promotion by inhibiting cholinergic receptors in the basal forebrain, and also present in the vascular system’s smooth muscle to regulate myocardial oxygen consumption and blood flow through the heart muscle.

Adenosine A2a Antagonism

The Adenosine A2a receptor is a GCPR receptor (PDB:3EML) with adenosine as the endogenous ligand.  A2a regulates myocardial oxygen consumption by vasodilating coronary arties, which may result in hypotension (decreased blood pressure).  In the brain, it regulates the release of neurotransmitters glutamate and dopamine, and has been indicated as a potential target for treating Parkinson’s Disease, addiction, and mood disorders.

XedTools 3.0 Released

The new version of our popular XedTools is now available. XedTools 3.0 includes new functionality and the latest version of our XED force field.

The new force field incorporates:

  • a completely analogue system for dealing with nitrogen atoms, enabling smooth transition from pyramidal to planar geometries
  • enhanced description of aromatic halogen interactions
  • support for some boronates and silicates.

The XedTools package consists of:

XedMin

XedMin is Cresset’s free ligand minimizer used by thousands of our customers.  This version includes important new functionality. A new command line switch enables the loading of a protein molecule so that ligands can be minimized within a protein context. Minimizing a set of docking poses in the XED force field can now be achieved using a simple script. Note that in this release the protein is limited to less than 15,000 total atoms (around 500 residues), is held completely static during the minimization and is not output at any stage.  Register for a free XedMin license here.

XedeX

XedeX is an integral part of all of Cresset’s applications; it is used to explore the conformations of molecules before adding them to databases or comparing molecules using fields. It is force field based so that all conformations are realistic, energy minimized structures. In our studies it performs excellently in reproducing bioactive conformations for molecules with less than 8 rotatable bonds. This version includes numerous tweaks to improve performance and an expanded ring library to include quinoline- and isoquinoline-containing structures.

XedConvert

XedConvert has been an integral part of our virtual screening system Blaze for some time but is a new addition to the XedTools package. Unsurprisingly, XedConvert is used to convert molecules between file formats and between 2D and 3D. It reads molecules in smiles, sdf, sdf3000, mol2, pdb and our own xed format and writes molecules in sdf, mol2 and xed formats. Given 1D or 2D data it will convert to 2D and 3D respectively, adding Cresset’s molecular fields as required. If you are planning on using XedMin to minimise ligands in the active sites of a protein then we recommend that you convert the protein in xed format first using XedConvert. As with all our command line tools, XedConvert can be combined with other applications in a pipe as it uses STDIN and STDOUT by default.

A free 12 month license to XedConvert is included with every request for a XedMin license, just register for a free XedMin license here.

KNIME Nodes

We are currently working to integrate the new features in this release of XedTools into our KNIME nodes. The current XedeX and XedMin binaries should work seemlessly with the existing release and we expect to have new nodes available shortly.

To register for a free demo of XedeX or take a free 12 month license to XedMin or XedConvert simply register here and we’ll send you a license file.