Cresset Unveils Spark – the Update to FieldStere, a Leading Bioisostere Software Tool

Enabling Medicinal and Computational Chemists to Find New Structures in New Chemical Space

Welwyn Garden City, UK (19th September 2012) Cresset, innovative provider of software and services for molecule designers, unveils Spark, the next generation of its bioisostere software tool FieldStere. Building on FieldStere’s industry-leading ability to find structurally novel biologically equivalent replacements for key moieties in molecules, this update provides powerful new capabilities including Cresset’s new XED3 force field, new clustering algorithms and access to ADMET and physicochemical property predictions on bioisosteric replacements.

sparkV10 interface and screenshot

Medicinal and computational chemists use Spark to generate novel and diverse active compounds by replacing sections of existing molecules with bioisosteric fragments. The results are used to create or improve IP positions and optimize leads while minimizing ADME and toxicity issues. Spark is available for deployment on standard desktop computers and can be integrated into workflow technologies. Spark will:-

  • Generate highly innovative ideas for lead molecules in new areas of chemical space, overcoming the ‘chemotype trap’.
  • Grow fragments to generate novel, drug-like molecules.
  • Filter results to find the bioisostere with the right mix of physicochemical properties and biological activity.
  • Tailor results by selecting the chemistry allowed for the replacement moieties.
  • Display results in detail side-by-side and cluster similar chemical scaffolds.
  • Search for moieties from real, published or unexplored compound databases or create custom databases based on proprietary chemistry.

Cresset CEO, Dr Robert Scoffin said, “This update to Spark reflects the new names of the molecule design tools in our Next Generation Chemistry Software portfolio. Spark builds on the excellent results of FieldStere to give companies improved IP positions by patent-busting or patent-expansion as well as benefiting from lower-risk and lower-cost strategies for the discovery of new chemical entities. Additionally, by exploring bioisosteric replacements and using field-similar rather than structure-similar molecules, Spark generates new leads, even in crowded therapeutic areas.”

Scientists interested in Cresset’s Next Generation Chemistry Software can download a free demo.

September 2012 Newsletter

sparkV10

Spark, the next generation of our bioisostere software tool FieldStere is now available. This update provides powerful new capabilities including Cresset’s new XED3 force field, new clustering algorithms and access to ADMET and physicochemical property predictions on all results.

Use Spark to generate new IP from published structures or scaffold hopping from a compromised series. Applying Spark to a completed project will improve your patent definitions and reduce the chances of losing your privileged position to a competitors bioisostere. Find out about what’s new.

See Spark in Action

We offer free demos on all our products free of charge. To try Spark for yourself contact us. See the power of Spark in this recent poster.

FieldStere Customers

FieldStere customers are entitled to a FREE upgrade to Spark. We’re sure you’ll find some great new features so be sure to upgrade soon. Send me a Spark upgrade license.

Presentations and Posters

If you missed presentations and posters at ACS Fall, EuroQSAR and EFMC-ISMC you can find them here:

> Disruptive Technology for Chemical Patent Fortification
> Computational Tools for Medicinal Chemists
> Optimizing Your Leads for Potency AND Drug Likeness
> Finding Novel Bioisosteres
> 3D QSAR – Why be Square?
> Rapid Technique for New Scaffold Generation

See upcoming events.

In The News

> New Drugs from Old, Innovations in Pharmaceutical Technology, Autumn 2012
> Focused Library Design Using Forge, Genetic Engineering News, September 2012
> Independent Review of forgeV10 by Chris Swain, Macs in Chemistry, September 2012
> David Bardsley Appointed as Sales Director

See all news from Cresset.

Spark Released

Spark is the next generation of our bioisostere searching tool “FieldStere”. Building on the excellent results that you have been getting with FieldStere we have introduced new science and an improved user interface with the release of Spark.

Our collaboration with Optibrium has enabled us to bring predictive ADMET models into the Spark results table. With this optional add on, every result in the table gets scored against every StarDrop model that you license or create. Once in the table you can use the predictions to filter or sort the results giving you a clear indication of the likely benefits and drawbacks of incorporating a specific bioisostere.

The Cresset proV10 range of products incorporates the next generation of our proprietary molecular mechanics XED force field. XED3 was first released with Forge and includes improved field patterns surrounding aromatic halogens, improved fields around kinase hinge binding moieties and a radical change in the handling of nitrogen. It has long been known that nitrogen atoms do not exist in exclusively planar or pyrimidal geometries yet all molecular mechanics force fields model it in one of these two states. XED3 breaks this mould allowing nitrogen atoms to flex between the two states in an analogue fashion as the degree of hybridization with neighboring groups changes.

FieldStere introduced the ability to view the results in clusters way back in version 1.1 and you’ve told us how much you value this feature. For Spark we’ve extended the clustering capability to give you multiple ways of doing the clustering making it easier than ever to find the best bioisosteres for your project. The new clustering algorithms give more control for both scaffold replacements and in experiments which grow molecules or otherwise introduce new terminal groups.

In common with Forge we’ve simplified the user interface providing clearer icons and a better interface for reading molecules. As you’ve come to expect from us we are still focused on making your experience as easy as possible so the popular wizard interface remains unchanged. The screenshot below should give you a flavor of what is new but please try it for yourself. All current FieldStere customers get a free upgrade so contact us to get your new license file and download.

sparkV10 interface and screenshot

Fast Computational Method for Fragment Growing and Joining Using Molecular Fields

Our presentation on ‘Fast Computational Method for Fragment Growing and Joining Using Molecular Fields’ by Dr Martin Slater, Director of Consulting, builds on the fragment growing article we published in November 2011.

To view Martin’s presentation, which was made at the CHI Structure Based Design conference in Boston MA, June 2012 click here:

SBDD_2012

What’s new with the Cresset product line up?

We have made some major changes to the names of our products recently and are thrilled to introduce a new suite of Next Generation Chemistry Software. The suite encompasses five products: Forge, Torch, TorchLite, Blaze and Spark. This new product line up is designed to fit more closely with your computational and medicinal chemistry needs and we encourage you to take a look and let us know what you think.

Some of the products have simply been re-launched with fire-themed names like Blaze and Spark, but others will show significant changes over previous products and now include exciting new features.  If you’re already using Cresset software or you’ve grown accustomed to the old product line, you might want to take a look at the product guide below to see how things have changed. We’re launching the new products together but it will take a few weeks for the developers to finalize all the releases so please bear with us during the change over.

Old Product Name New Product Name Description and Features
FieldTemplater and FieldAlign together Forge Forge is a powerful computational suite to understand SAR and design. It brings together all the functionality of FieldAlign and FieldTemplater together with new science and new capabilities. It helps you:

  • Decipher complex SAR and communicate the results.
  • Design better molecules based on predictions you can trust.
  • Prepare detailed pharmacophores.
  • Virtually screen 10 000 compounds on your desktop.
  • Generate ADME and off target activity profiles.
FieldAlign Torch Torch is a powerful design and 3D SAR tool for medicinal chemists. Torch represents a new opportunity for our medicinal chemistry customers to use a product that is dedicated to the tasks that you want to do.  It helps you:

  • Perfect the design of new lead compounds, exploring a range of lead optimization ideas.
  • Get the most from your lab time by prioritizing compounds for synthesis.
  • Design focused libraries for synthesis or initial screening.
  • View ADME profiles and off-target activity prediction on all designs.
  • Use powerful predictive QSAR models from Cresset’s Forge.
FieldView TorchLite  TorchLite is a free 3D molecule viewing, editing and drawing tool.  It helps you:

  • Sketch your chemical series to study how field and activity patterns are related.
  • Import and compare up to 10 000 compounds from SDF, MOL2 or Cresset applications.
  • Convert from 2D to a minimized 3D conformation.
  • Clone and compare molecules side by side or overlaid using Cresset’s unique field technology.
  • View virtual screening results.
FieldScreen Blaze  Blaze is an amazing ligand based virtual screening tool.  It helps you:

  • Increase the diversity of your project’s leads and backups.
  • Jump into new areas of chemical space.
  • Improve the lead-like properties of hits.
  • Virtually screen 10 million structures in a few hours.
  • Design diverse libraries of compounds for synthesis or biological screening.
FieldStere Spark Spark is an exciting and powerful way of generating novel and diverse structures for your project. It helps you:

  • Generate highly innovative ideas for lead molecules in new areas of chemical space, overcoming the ‘chemotype trap’.
  • Use filters to find the results with the right mix of physicochemical properties and biological activity.
  • Tailor results by selecting the chemistry allowed for the replacement moieties.
  • Visualize results in detail side-by-side, or cluster similar chemical scaffolds.
  • Search for moieties from real, published and unexplored compound databases or create your own custom databases.
Xed Tools Xed Tools Nothing’s changed here!  The XED molecular mechanics force field is still at the heart of Cresset’s field technology and you can still use Xed Tools for conformation generation and ligand minimization.

Still have more questions?  Take a look at the FAQs below, or contact us to learn more about the product line changes and how they work for you.

I already use some of the old products.  What happens to my yearly license?

Nothing changes for now.  You can continue to use your current software license(s) without any interruption in service. When your license is up for yearly renewal, we’ll be in touch to see how your needs align with the new products and then you can decide which products work best for you.

Do these new products work with the same operating systems and interfaces as the previous product line up?

Yes, all of new products work exactly the same way as they did previously.  The table below gives you a good idea of which products work with which operating systems and interfaces.

Operating Systems Interfaces
Product Windows Linux Mac
Forge
Torch
TorchLite
Blaze
Spark
Xed Tools

I just tried a demo of one of the old products. Do I need to try a new demo the new products too?

That depends on which product you’re interested in. If you’ve previously tried FieldTemplater or used FieldAlign and wanted to do more then you will definitely want to check out a new demo of Forge because we’ve added lots of cool new features that were designed specifically with computational chemists in mind. If you’ve tried a demo of FieldStere, FieldScreen, XedTools, or any of the interface options you probably don’t need a new demo right now because all we’ve changed is the product name.   Feel free to contact us if you have questions about your product demo.

Why did you rename the products with fire-themed names?

We’ve been planning to align our product line up more closely with your needs for a long time, and with the launch of Forge, we decided it was also a good time to update a few other things.  Plus we love the fact that our fiery Cresset logo now matches our new product names!

Some of the links on your site don’t work anymore.  What’s happening?

Sorry, this is our mistake and we apologize for the inconvenience. We’re doing our best to ensure that our website gets updated right along with the product changes but you’ve obviously found a mistake.  If you find a broken link, or other problem, please let us know and we’ll fix it right away.

 

November 2011 Newsletter

FieldStere V3.0 ReleaseFieldStere is now better than ever.  Click here for an overview of the changes, or check out the case studies and videos below for details.  Haven’t tried FieldStere yet?  Request a free evaluation today.


FieldView: Tips & Tricks Part 2

FieldView is our extremely popular 3D  molecular viewer and editor.  Last month we featured tips for using the viewer, and this month we’ve included a quick guide to using the editor.   FieldView is available as a free download to all users, whether industrial or academic, so if you haven’t given it a try, click here to get it for free.

Learn more about using FieldView here…

Videos: See FieldStere V3.0 in Action

We’ve created three brief video demonstrations to clearly illustrate the new features of FieldStere.  We’ll cover molecular comparisons, user interface improvements and the new database updater in these demos.  If you still have questions about FieldStere V3.0, you can always contact us at support@cresset-group.com

Check out the videos  here…

8 Questions with Dr. Rae Lawrence

Rae Lawrence is Cresset’s hard-working North American Sales Manager.  With over 10 years in the chemistry software business and a PhD in computational chemistry, she’s an excellent customer resource.  She’s also a well loved colleague with some strong opinions on the state of drug discovery today, and an interesting history as a theater star.  Curious?

Get to know Rae Lawrence here…

FieldStere: New Features at work

Because this new release includes such valuable changes to the software, we though we’d give you a few examples of how these changes will work in practice.  Click the links below to see how FieldStere enables fragment growing with protein kinases and chemotype morphing with Beta Secretase.

FieldStere V3.0 New Features Videos

FieldStere V3.0 includes some major changes and we’re pretty excited to share them with you.  Take a look at the video demonstrations below for a brief introduction to comparing multiple molecules, interacting with the improved interface and using the new database updater in FieldStere V3.0

If you have trouble viewing these videos here, please click here to view them on YouTube.

Part 1: Comparing Multiple Molecules

Part 2: The Improved User Interface

Part 3: The Database Updater

Still have questions about FieldStere or the changes we’ve made?  Contact us at support@cresset-group.com and we’ll be happy to help.

FieldStere V3.0 Example 2: Fragment Growing

FieldStere V3.0 includes several improvements to the scientific capabilities of the software.  In this second example of FieldStere’s updated abilities, we look at how fragment growing can be used with Mitogen-activated Protein Kinases (P38) to generate novel, drug-like molecules.

Background

P38 (mitogen-activated protein kinases) are a set of protein kinases (Alpha, Beta, Gamma, Delta) which participate in signalling cascades controlling cellular responses to stress stimuli and are ultimately involved in cell differentiation and apoptosis.  The stress stimuli include responses to cytokines, heat shock, osmotic shock and UV irradiation.  These kinases are being recognised as important therapeutic targets: A P38 Gamma inhibitor has recently been approved for idiopathic pulmonary fibrosis (IPF) and P38 alpha inhibitors are potential anti-inflammatory agents eg PH-797804 which are currently in clinical trials for COPD.

Structures

A large number of P38 alpha inhibitors are known and for many of these, the X-ray crystal structures for the ligand complexes are available.  P38 alpha is a particularly plastic protein with inhibitors known to bind in a variety of different protein conformations.  This wealth of data extends to large inhibitors as well as small fragments.  Three example inhibitors are shown below in Figure 1.

Fig.1 Example P38 alpha inhibitors

Compound (3) is a fragment which specifically binds to the inactive form of P38 alpha known as the ‘DFG-out’ kinase protein conformation.  In this form, the activation loop is distorted and the catalytic residues are displaced from their usual position and are thus incapable binding ATP (Figure 2).

Fig.2 DFG-out P38 fragment inhibitor (PDB: 3K3I)

Unfortunately, this attractive non-competitive form of inhibition, although relatively rare, is not unique, and inhibitors which bind this conformation tend also to be inhibitors of protein kinases, which can adopt this conformation (eg Imatinib inhibits both c-abl, c-kit and PDGF-R).

In contrast, inhibitors (4) and (5) are more selective for P38, though they are ATP competitive and interact with an active conformation of P38.  They are selective due to the plasticity of P38 particularly in the hinge region.  The hinge glycine residue allows a 180 degree flip of its peptide bond such that a switching of the H-bond donor/acceptor pattern is required by the inhibitor (Figure 3).

Fig.3 Selective P38 inhibitors (4, PDB: 3ROC) and (5, PDB: 3HUB) overlaid with the fragment (3)

We can demonstrate the utility of FieldStere in a fragment growth application here by using the compounds 3 and (4 or 5).  The combination of this fragment with these selective inhibitors could potentially yield novel selective inhibitors which are non-ATP competitive.  Growing towards the hinge region will also increase the potency of the fragment (compound 3).

Process

For this experiment a dummy atom on compound (3) was used as the starter molecule for the process and compound (4) was used as the reference against which the resultant molecules would be partly scored (actually 3 and 4 were weighted using a 1:4 ratio of their contribution, respectively).  Effectively, fragment (3) was grown, by adding new fragments, guided by the field similarity to compound (4).

The results were limited by imposing some restraints eg (i) the fragment size limit was removed so that relatively large fragments could be obtained (ii) the fragment had to contain a ring and (iii) number of rotatable bond in the fragment was reduced to 3 or less, finally (iv) the p38 DFG-out protein conformation of the reference was used as an excluded volume.

Results

Selected examples from the results of the experiment are shown in Figure 4.

Fig.4 Example FieldStere fragment growth results

The resulting output molecule ideas are relatively compact and drug-like, chemically sensible and appear reasonably synthetically tractable.  The 3D overlays of the compounds fit extremely well to the merged reference and fragment template (Fig.5).

Fig.5 Example FieldStere fragment growth results in 3D. The red circle in the fragment reference highlights the dummy atom (fragment to be replaced).

Interestingly, the field point representation reveals a dipole feature present across all the compounds. This dipole is consistent with that produced by DFG-out compounds such as Imatinib which may allow a Phe residue (from the DFG motif) to wrap the inhibitor.

In the context of the protein, all the examples are capable of mapping to the flipped-hinge protein conformation and thus have a potential selective handle.  Furthermore, each example is also consistent with an inactive DFG-out protein conformation ie will likely be ATP non-competitive in their mode of action if they inhibit this kinase.

Conclusions

Fragment based drug discovery is an increasingly popular technique to parallel the more conventional HTS paradigm.  Fragment joining and fragment growth are essential tools in the armoury of practitioners in this new art.  The fragment growth example described here demonstrates the flexibility of this new release of the FieldStere software, the power of fields, the broad scope and applicability in this and other areas of drug discovery.

Still have questions about FieldStere?  Contact us at support@cresset-group.com, and we’ll be happy to help.

Cresset Announces the Release of FieldStere V3.0

Welwyn Garden City, UK (1st Nov 2011) Cresset is pleased to announce the release of a new version of popular bioisostere replacement tool, FieldStere.  FieldStere is a fast and powerful software tool which uses Cresset’s innovative field-point technology, together with a database of molecular fragments, to help guide drug discovery projects and generate new intellectual property.  Version 3.0 includes impressive updates to the science and user interface, and constitutes the most significant scientific update to FieldStere since its introduction.

FieldStere V3.0 now enables researchers using fragment based drug discovery protocols to grow initial leads computationally, giving significant boosts to productivity and diversity. Importantly, FieldStere works both on projects operating with protein crystallography support and on those without these resources, an area currently under supplied with computational techniques. Unlike traditional pharmacophore approaches, FieldStere uses molecular interaction with proteins as a core descriptor rather than 2D structure, enabling diverse active molecules to be described as similar.

“This version of FieldStere introduces major enhancements to the fundamental science. The ability to grow from fragments to introduce and refashion interactions made by other molecules will add significantly to the computational arsenal of Fragment Based Drug Discovery researchers.” said Dr Mark Mackey, CSO of Cresset.

FieldStere V3.0 is available as a desktop application or command line interface on Linux, Windows and now also on Mac machines. Alternatively, FieldStere may be accessed through Cresset’s Professional Services Division. A free evaluation is available through the Cresset website.

To learn more about the new features in FieldStere V3.0, please see these video demonstrations, and read these case studies on chemotype-morphing and fragment growing.technology

CASE STUDY: Using FieldStere for Scaffold Hopping

The metabotropic glutamate receptors (mGluR) have become popular and important targets in small molecule drug discovery. In particular there is increasing interest in and clinical trials of mGluR5 antagonists in the treatment of anxiety, depression, pain, gastro-esophageal acid reflux disease (GERD), Parkinson’s disease, epilepsy, and Fragile X Syndrome (FXS). The allosteric binding site of mGluR5 , located within the transmembrane region, is generally considered to more likely to lead to effective medicines than other binding sites

One of the prototypical small molecule mGluR5 allosteric antagonists is MPEP (2-methyl-6-(phenylethynyl)pyridine). Using MPEP as a starting point we searched for bioisosteric replacements that would introduce novel IP in this well worked area. In both cases, bioisosteres were retrieved using FieldStere.

FieldStere searches a up to 600,000 fragments for bioisosteres that exhibit similar shape and electronic properties when placed in the context of the final molecule. FieldStere uses molecular interaction Fields to represent the key binding interactions of a molecule giving a close approximation to the protein’s view of a potential ligand. Using the Field descriptors in FieldStere gives a wide range of bioisosteres, from the obvious replacements, through less obvious to completely non-obvious.

Using FieldStere on MPEP, two separate experiments were performed. Below are shown a selection of the results obtained when searching for replacements for the central alkyne (left column below) and for the pyrido-alkyne section of the molecule (right column below). In both cases unreported, novel structures were found together with a significant number of previously reported actives. The position of the found actives was irrespective of the 2D similarity of the final molecule to MPEP.