A Novel Series of Non-Peptide Small Molecules for Protein-Protein Interactions

Senexis scientists had found a series of peptides with promising biological activity. Cresset’s software was used to identify drug-like chemotypes to mimic the activity of these peptides. The work resulted in novel lead molecules for Senexis.

Senexis Ltd is a small molecule drug discovery company that has discovered novel compounds to treat diseases resulting from the toxicity of amyloid-like proteins. They had developed a series of ‘meptides’ (N-methylated peptides) that block the aggregation of β-amyloid. An example ‘L-meptide’ search molecule is shown in figure 1, below.

Example L-meptide
Figure 1: An example ‘L-meptide’ search molecule from Senexis Ltd., used as the basis for finding non-peptide small molecules with similar activity.

Senexis asked Cresset to find novel series of non-peptide small molecules that mimics the activity of the ‘meptides’. Cresset’s molecular field technology is ideal for such a purpose.

Cresset’s patented set of XED molecular mechanics algorithms describe molecules based on their molecular field, rather than chemical structure. The resulting field point descriptors of molecules give a powerful basis for analyzing and comparing molecules based on their activity.

Once a molecule has been defined according to its field pattern, it is possible to look for compounds with new chemistry that have the same activity, despite being from a different structural class.

The first step was to use torchV10 to find the best conformation for four of the meptides. A β-sheet conformation was assumed, the molecules were aligned and the field pattern was calculated for each meptide.

The aligned meptides were used as field seeds in Blaze (the new name for FieldScreen), Cresset’s ligand based virtual screening tool. Blaze compared the meptide’s fields to Cresset’s field database of 1M commercially available molecules. Cresset scientists reviewed and analyzed the hits.

Matches containing interesting and novel chemistry were reported back to Senexis for their review. Three of the interesting new chemotypes whose fields matched the input seed field are shown in figure 2, below.

Three interesting new chemotypes
Figure 2: Three of the interesting new chemotypes whose fields matched the meptide seed field, identified using Blaze.

A further field seed from a pyridazine structure derived from RS0406, a known small molecule inhibitor, was then incorporated into the study. Results from a Blaze field search with this seed reinforced confidence in the validity of the new chemotypes.

Following this study, Senexis embarked on a program of medicinal chemistry and biological testing that resulted in two distinct chemotype sets. Cresset used Forge (the new name for FieldTemplater and FieldAlign) to produce templates for four active structures (two from each set) to find the common field pattern across all of the conformations and from that deduced the bioactive conformation.

Two active chemotype sets
Figure 3: Two active chemotype sets from Senexis and their bioactive conformers, found using forgeV10.

Further searches using these more reliable field patterns from the bioactive conformations revealed more information and ideas for the Senexis chemists to work with. Their current lead molecules are SEN1269 and SEN1186, the core of which is shown below.

Core of SEN1269 and SEN1186
Figure 4: The core of SEN1269 and SEN1186, the lead molecules identified by Blaze.

Accelerating Ligand-Based Virtual Screening

Today the UK’s most powerful GPU-based supercomputer, ‘Emerald’, will enter into service alongside the ‘Iridis 3’ system at the Science and Technology Facilities Council’s Rutherford Appleton Laboratory (RAL) in Oxfordshire, UK. These two High Performance Computing systems will give businesses and academics unprecedented access to super-fast processing capability.

Cresset is collaborating with the high performance computing group at the University of Bristol, UK to implement new GPU based algorithms within the core of our field technology. The following poster will be presented at today’s meeting. For further details of our project with the University of Bristol refer to our Fields at Warp Speed blog post.

Accelerating Ligand-Based Virtual Screening

Mark Mackey†, Simon McIntosh-Smithµ, Simon Krige†, Rob Scoffin
†Cresset Biomolecular Discovery Ltd, BioPark, Broadwater Rd, Welwyn Garden City, Herts, AL7 3AX, UK
µDepartment of Computer Science, University of Bristol, Woodland Road, Clifton, BS8 1UB, UK

Introduction

It has long been known that small molecule drugs are recognized by and bind to proteins on the basis of their 3D electronic and shape properties, yet the drug discovery cycle has traditional described and protected 2D structures.

Cresset is using field point descriptions of molecules to close the gap between chemistry and biology, bringing the features that are recognized by proteins to the desktop of our customers.

Field Points

Field Points are a condensed representation of electrostatic, hydrophobic and shape properties (protein’s view).

Molecular Field Extrema
Field Points

Molecular Similarity Scoring Algorithm

Given an alignment:
– For a given field point on molecule A, calculate what the field value is at the corresponding point in molecule B. The score of the field point is the product of its size and B’s field value.
– Repeat for all field points on A and calculate the sum of scores
– Repeat for the field points on B sampling the field of A, and normalise to a similarity

MolecularAlignmentAndSimilarities

Results

Current Situation

Large database of molecules (~5million)
– Compute time: 2-5s per molecule on a single CPU core
– Full screening takes ~35hours on 200 CPUs
– Full screening costs ~$500 on CPU

FieldScreenDB

Using GPUs and the Emerald Cluster

We have run the prototype FieldScreen GPU port on Emerald nodes. Speedup results are relative to the serial code running on 12 Intel i7 CPU cores.
– Using OpenCL: currently ~40x faster for a GPU vs a CPU.
– Full screening:
~$20 on GPU (25 times cheaper than CPU).
~30min using all Emerald GPUs!

NumberOfGPUs

Conclusions

The Emerald Cluster is giving us the opportunity to screen large virtual libraries of compounds (> 100m compounds) in very little time. The speed and cost advantages of GPUs have made it our technology of choice.

Acknowledgements

Funded by a TSB Knowledge Transfer Partnership.

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.

 

FieldScreen v2.6.0

FieldScreen 2.6.0 has been released. A completely new interface heralds significant improvements to the performance and user ability of our highly effective virtual screening application. Specific improvements include:

  • A new conformation hunting algorithm for molecules containing flexible rings
  • Full support for the upload of compound collections as smiles strings
  • Faster result retrieval
  • Improved interface to FieldView to enable submitting virtual screening experiments straight from our popular molecule viewer and editor
Screenshot of elements of FieldScreen 2.6.0 interface

Screenshot of elements of FieldScreen 2.6.0 interface

Drug Repositioning – IMPDH

Inositol monophosphate dehydrogenases (IMPDH) are vital enzymes in the production of GMP, GDP and GTP. IMPDH is important for cell growth and its inhibition is potentially useful in immunosuppression, anticancer therapy, psoriasis, rheumatoid arthritis and antiviral chemotherapy.

Our client, a small biotechnology company, wished to find new candidates for IMPDH from existing drugs that had been developed for other indications. Such compounds are more likely to be well tolerated and easily deliverable with good ADME and toxicity profiles, and were therefore lower risk candidates.

Six known human IMPDH inhibitors (four of which are shown below) were used to Field search the World Drug Index (WDI). The putative bioactive conformations of each ligand were derived using FieldTemplater to compare the six known ligands with ligands from available X-ray structures. 14 seed structures, covering all the putative bioconformers were then screened against the whole database using FieldScreen. The top 1,000 results from each search were then analysed to find the drugs that were common to as many of the seeds as possible.

4 IMPDH actives used as seeds

19 drugs were found that were common to 10 or more of the seeds. 13 of these are shown below:

13 result molecules

It is striking that these drugs are associated with therapeutic actions that could be related to the known action of IMPDH (with the possible exception of the relaxants). Detailed investigation of a related series of IMPDH inhibitors has revealed that the oxazole moiety can act as a potential source of reactive meta
bolites, which can cause toxic side-effects (Beevers 2006). Significant resource has been employed to replace this undesirable moiety by various groups. It is notable that none of the drugs identified by Cresset contains this moiety. Further investigation of this list has not been possible but one literature reference has been found that associates omeprazole and other HK-ATPase inhibitors with immunomodulation (Peddicor 1999).

References

Beevers et al. Bioorganic & Medicinal Chemistry Letters 16 (2006) 2535-2538

Peddicor T. E., Olsen K. M., Collier D. S. (1999) Crit. Care. Med. 27 (1): 90-4

 

Download this article in PDF format here.

FieldScreen 2.5.0 released

New release of FieldScreen, efficient ligand based virtual screening. This release includes major improvements for system administrators and users.

New features in the latest release of FieldScreen

The latest version of FieldScreen brings significant improvements in system management and major enhancements in result visualisation with FieldView 1.1.0.

FieldScreen 2.5.0, new management features

  • Faster – new infrastructure and file formats for compound collections make this release significantly faster than previous versions
  • Significantly reduced disk space requirements using new compression tools
  • New easy to use web interface for FieldScreen system settings

FieldScreen 2.5.0, new user features

  • New FieldView application for viewing Virtual screening results
  • Visualise each 3D result side by side with a 2D representation
  • Every result is reported together with TPSA, wcLogP, MW, Rule of fives violations etc
  • Interactively filter the results using any sdf tag or using the physical properties calculated by FieldView
  • View molecular fields around every result as points or surfaces, cross compare search queries and mutiple results using fields

New Services Launched

New Cost Efficient Lead Finding and Optimization Services Launched

Cresset specializes in the use of molecular Fields to help identify novel active chemistry across any target family. We have an impressive track record of discovering and optimizing novel active leads for customers built over 8 years.

Cresset has a success rate of over 80% across a wide range of target classes, on behalf of a range of customers from major pharmaceutical companies to small biotechs.

Cresset can now offer a quick, easy and cost-effective service to increase the diversity and innovation of your lead series. Using our Field based tools we can find a range of likely bioisosteres with diverse chemical scaffolds that you can use for screening assays, lead optimization, scaffold switching or repositioning, whether or not you know the structure of your target.

We have worked hard to make this service affordable, secure and quick so everyone can benefit from it.

Please click here for more information or contact us about a free, confidential consultation. We would welcome the opportunity to discuss how Cresset could help you in your drug discovery projects.