Forge V10.3 released

We are delighted to announce the release of a new version of Forge, our computational chemistry workbench for ligand-based design. This version, V10.3, includes over 70 new or improved features.

The development of our applications is always guided by our customers and this release is bursting with features that you have asked for. A few of these are described below but there is no substitute for using the software for yourself to see the new features in action.

Release highlights

  • Support for multiple activities in Activity Miner – find and decipher selectivity as well as activity cliffs
  • Automatic enumeration of unspecified chiral centers
  • Improved conformation hunt settings that gives significantly fewer, lower energy conformations.
  • New integrated FieldTemplater module – find a detailed pharmacophore from diverse ligands
  • Integration with Blaze for virtual screening – submit molecules to Blaze and retrieve results straight into Forge
  • New radial plots enable rapid assessment of compounds properties against project or corporate profiles

Activity Miner

Activity Miner has been a huge hit since its release last year. You told us that you enjoy the powerful yet intuitive interface, that it has helped you to find and understand critical regions in your SAR and that it has helped your medicinal chemists rapidly assess the SAR landscape of projects. However, the number one request has been for selectivity cliffs – the use of multiple activities to look for changes that disproportionately change one activity relative to another. In this release of Forge we are have included this functionality.

Multiple activities

Activity miner now supports multiple activities and displays activity cliff information for all activities and all compounds in a matrix of all compounds or relative to a single compound. All the new data created a major challenge – how were we going to present multiple activity cliffs using multiple similarity metrics for many compounds in an easy to understand way? However, we think we have succeeded in the task that you set us (below) but please tell us how well it works for you on your data!

Forge_10.3_release_am_pic

Use 2 activities or even more!

There is more new science in this release beyond selectivity cliffs. In particular we’ve been looking at our treatment of molecules with an unspecified chiral center and how we perform conformation hunting. In this release we now enumerate all the possibilities in molecules loaded with unspecified chiral centers. Like selectivity cliffs, this feature has been a high priority for our users and we are delighted to introduce this new functionality.

Conformation hunting

Conformation hunting is critical to our alignment methods and hence always something that we are looking to improve, even though independent tests show that our performance is one of the best. Our research has shown that we can reduce the number and increase the quality of conformations we use with a couple of small changes to our settings. By improving the minimization of conformations, combined with taking a smaller energy window for accessible conformations, you get significantly better populations in most cases. However, these changes come with a penalty – the time taken for this type of conformation hunt is increased. As a result we’ve changed how our default ‘Accurate’ methods work to use the new settings but retained the previous settings for ‘Quick’ and ‘Normal’. The great thing is that with our standard calculation dialog box you can choose your own settings and have these quickly available for later use.

Forge_select results quality desired

User interface

The new user interface includes custom plots, radial plots of properties, a manager for activity and the associated error data, ribbon view of proteins and auto-color of selected molecules which are requests from customers. However, one new feature that we wanted for use on our internal work, and especially our consulting projects, is a simple script interface to changing some of the values in the molecule table.

Forge_10.3_release_3D_pic

Column script editor

The column script editor provides a JavasScript interface to molecule and table data and enables modification, formatting or creation of values in the table. A simple example might be to remove the ‘>’ symbol from activity values before using them in a 3D-QSAR experiment, or coloring all values in a column called ‘HERG_IC50’ that are below 10 as red. Once developed (and we are happy to help you get your script working quickly), these scripts can be set to run on every project or exported for use by colleagues running Forge or Torch.

Forge_10.3_release_script_editor

This release is a major advance for Forge so we encourage you to upgrade at your earliest convenience.

If you are not currently a Forge customer then now is a great time to try a free demo.

Contact us if you have queries relating to this release.

Presentations from Cresset’s user group meetings 2014

Cresset’s North American user meeting was held on June 11th. We were kindly hosted by Novartis in their Cambridge, MA facilities. The European meeting took place the following week on June 19th – 20th at Madingley Hall, Cambridge, UK.

Between them, the meetings were attended by a diverse group of computational and medicinal chemists from academia, industry and patent offices.

Links are provided below to the non-Cresset presentations we have permission to publish plus presentations by Cresset.

North American meeting – non-Cresset presentations

European meeting – non-Cresset presentations

Cresset presentations from North American and European meetings

Workshops

Both the North American and European meetings incorporated software workshops for delegates to receive hands-on software training on Torch with Activity Miner, Forge and Spark. Advanced workshops were also run for experienced users to learn more about recent new features in the software.

Contact us if you are interested in contributing to the scientific program of the 2015 Cresset user meetings.

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Delegates at European user group meeting at Madingley Hall, Cambridge, UK
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Delegates being guided through software workshop in North America
(click to enlarge image)

Centre for Chemical Biology & Therapeutics at inStem licenses Cresset’s computational tools for lead optimization and identification

Cambridge, UK – 2nd June 2014 – Cresset, innovative provider of computational chemistry software and services, is pleased to announce that the Centre for Chemical Biology and Therapeutics (CCBT) at The Institute for Stem Cell Biology and Regenerative Medicine (inStem), a state-of-the-art research institute in Bangalore, India, has taken a three year license for use of Cresset’s Forge and Spark software tools for lead optimization and identification. The CCBT, which is directed by Prof. Ashok Venkitaraman (University of Cambridge) in an international collaboration between Cambridge and inStem, seeks to pioneer new approaches for chemical biology and therapeutics through the development of new methods for small-molecule drug discovery. Cresset and Forge will be used in the new computational chemistry group in the CCBT.

Dr. Kavitha Bharatham, who leads the computational chemistry team in CCBT, says “Having used Cresset’s software in my previous role, I am very keen to apply it to our work at CCBT. My experience with Forge and Spark makes me confident that they will be valuable tools for our research. The support I have received from Cresset staff has been excellent, and I am very pleased to introduce their computational tools to CCBT for our lead optimization and identification projects. I am confident that we will achieve our goals.” Prof. Ashok Venkitaraman, who directs the CCBT, adds, “The CCBT aims to pioneer innovative new approaches for using chemical tools to understand the biology of human diseases like cancer, and to develop new avenues for therapy. I am pleased that we will be licensing Cresset’s software for our work.”

“We are delighted that the CCBT at inStem has chosen to work with Spark and Forge,” says Dr David Bardsley, Cresset’s Commercial Director. “Spark will enable them to generate novel and diverse structures and to use reagent databases to inform synthetic decisions. Forge gives the CCBT control and insight into their activity data enabling them to plan the direction of their project with confidence.”

New release of Cresset’s Blaze improves speed and scope of virtual screening and makes it available in the cloud

Cambridge, UK – 6th May 2014 – Cresset, innovative provider of computational chemistry software and services, announces 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 with third party software and an improved security system.

In addition, computational chemists will benefit from free access to a new, fully-functional Blaze Cloud demo server that demonstrates the simplicity of a Blaze virtual screening experiment. Blaze SaaS, provides the ability to search millions of commercially available compounds using an encrypted web browser session.

“Blaze uses the shape and electrostatic character of known ligands to rapidly search large chemical collections for highly diverse lead-like structures,” says Dr. Mark Mackey, Cresset’s CSO. “It is excellent for finding novel lead-like hits from known actives, replacing peptides with non-peptides or steroids with non-steroids.”

“This new release dramatically improves the speed and scope of Blaze, and includes enhanced integration and security in response to customer feedback,” says Dr. Tim Cheeseright, Director of Products at Cresset. “Blaze SaaS gives you a pay-as-you-go way to access Blaze via the cloud, from a web portal, without the need to invest in hardware. This is particularly useful for those customers who want immediate access to virtual screening with no capital or on-going infrastructure costs.”

Blaze V10.2 features:

  • A new search algorithm that enables full 3D assessment of molecules at four times the speed, enabling the processing of larger databases of over 10 million compounds.
  • A new RESTful web service providing easy integration with Forge, KNIME and Pipeline Pilot and custom software solutions.
  • Simplified security features that are easier to unify with corporate policies, in response to customer requests. This makes it easier to roll out Blaze across corporations.
  • A free demo server, enabling you to search a small collection of compounds using the standard search cascades and manage compound collections. Register for your username and password at the Blaze demo signup page.

Read more about the new release of Blaze V10.2.

Blaze SaaS integrates with Forge

Drug discovery with data

In the second part of Scientific Computing World’s series on computational chemistry, Sian Harris looks at the role of modelling and high-quality data in the pharmaceutical industry.

Read this second part.

Read the first part ‘Compound benefits’.

New release makes wide range of Cresset’s drug discovery software available through Pipeline Pilot interface

Cambridge, UK – 27th February 2014 – Cresset, innovative provider of computational chemistry software and services, is pleased to announce the release of our latest set of Pipeline Pilot components V2.0.0, including new tools for 3D visualization of field patterns, SAR data analysis and 3D-QSAR modeling.

“Chemists can now access even more of Cresset’s advanced technology through Pipeline Pilot,” says Dr. Tim Cheeseright, Director of Products at Cresset. “This release gives the benefit of new ideas and insight for their drug discovery projects within a familiar interface. All of Cresset’s Pipeline Pilot components are free for existing users of Cresset’s software.”

The new Activity Miner component finds activity cliffs in your SAR data. It uses the disparity between two molecules to highlight where small changes in structure result in disproportionately large changes in activity. Uniquely, Activity Miner operates using both 3D and 2D similarity metrics to assess the change in a structure, enabling a better understanding of the reasons for the change in activity. Pipeline Pilot’s advanced reporting and visualization capabilities can be used to view this data, e.g. as heat maps, so you can quickly focus on the most important regions of SAR in your data set.

New 3D-QSAR components bring a combined alignment and 3D-QSAR capability based on accurate molecular electrostatics, something previously unavailable in Pipeline Pilot. Users can generate 3D-QSAR models, view the models to gain information about the field patterns required for activity in their data set, and predict the activity of new compounds.

New XedeX and XedMin components simplify access to Cresset’s advanced XED force field minimization and conformation searching engine, allowing you to use our force field anywhere along an existing protocol.

It is now simple to find bioisosteres, jump series and gain ideas for what to make next during lead optimization with the updated versions of the Spark components in this release.

The new Viewer component allows the visualization of 3D electrostatic field patterns around molecules to be easily accessed at any point within Pipeline Pilot, bringing the power of visual field analysis to your 3D workflows and giving a new dimension of understanding for Pipeline Pilot users.

Pipeline Pilot Heat Maps
Cresset’s new Activity Miner component for Pipeline Pilot finds activity cliffs in your SAR data. Pipeline Pilot’s advanced reporting and visualization capabilities can be used to view this data, for example as heat maps, enabling you to focus on the most important regions in your data set.

Compound benefits (part 1)

I’m pleased to have had the opportunity to contribute to the ‘Compound benefits’ article in Scientific Computing World. This is the first of two articles on computational chemistry which you can read here.

Read part two here.

Mark
Mark Mackey
CSO

Focused screening library design – enhancing your expertize

Library design‘ is a phrase that can encompasses many approaches and workflows including the design of screening libraries or the design of lead optimization libraries. We offer computational chemistry software and services that can help you with many of these design processes. Here we detail an approach that we have used successfully for the design of ‘focussed screening libraries’. That is libraries aimed at improving the hit rates of high or medium throughput screening for specific biological entities or families or at difficult targets such as protein-protein interactions.

Our approach to the design

Approach to design
Figure 1: Cresset’s approach to library design
In our view the first step in designing something new is to thoroughly understand what has gone before. However, no one wants to spend weeks studying past history when we could be getting on with a design! Usually we take a pragmatic approach – understanding what has gone before is critical to success but must be accomplished in as short a time as possible. We always detail the time that we are going to spend on this stage and the impact that it is likely to have on the final design. Usually we can shortcut the process by working closely with our client; we can use their knowledge to fast track our own. Together we often both gain deeper insight than we achieve separately.

The second stage is the most critical for the outcome of the project – idea generation. We find that our ideas materialize as we review and understand the previous work, including relevant ligands or crystal structures of the biological targets. As our analysis approaches its conclusion we begin generating and refining our ideas on new chemical entities that could form the heart of a new design. Of course every project is different but one common theme is that the first set of compounds are rarely the best and the ideas have to be refined and improved. As this progresses we take careful consideration of the potential to decorate cores with different R groups, the capabilities and thoughts of the synthetic chemists that will create the final compounds and the project brief. Bringing all these different components together is critical to success.

Why use Cresset?

library_design_history
Figure 2: Active compounds from focussed screening libraries designed by current Cresset staff
Customers come to us to combine our approach with their own expertize. As an independent unit we are often asked to think ‘out of the box’ to create truly innovative products. This could be on well worked targets, orphan receptors or one of the more challenging projects which require more resources than can be accommodated internally.

We have extensive library design experience using different approaches.1, 2 Our custom designs have been used throughout our industry from large pharmaceutical companies to small biotechs with diverse hits being obtained in kinases, GPCRs and ion channels.

Our range of software products inspire and inform our customers to generate the best molecules that they can and we use the same applications on our projects. However, our service offerings benefit from early access to new science features in the main software products (such as Activity Miner) and from access to unreleased software and cutting edge science. For example the ability to study the electrostatic environment of a protein active site and relate proteins using this description.

References

1. Thematic Analysis : A Chemogenomic Approach to GPCR Drug Discovery
2. The Design and Application of Target-Focused Compound Libraries

Computational Chemistry Software Suite Chosen by Medical Research Council Technology

Medical Research Council Technology (MRCT) has chosen to license Cresset’s computational chemistry software suite.

“The decision of MRCT to work with Cresset’s computational chemistry software suite demonstrates the value and insight our products bring to researchers,” says Dr. David Bardsley, Cresset’s Commercial Director.

Dr. Kristian Birchall of MRCT says, “We are pleased to be working with Cresset’s software. This provides us with intuitive molecule design, a powerful ability to understand SAR and design plus a fresh way for generating novel and diverse structures for our projects.”

Dr. Bardsley adds, “Cresset’s software works at the meeting point of chemistry and biology, giving chemists a way of understanding their molecules in terms of biological activity. Our technology and services are providing companies with the right information, wherever they sit in the drug design workflow.”

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.