Video tips for September Design a Molecule

Cresset and Redx Pharma announce Major Drug Discovery Collaboration

Welwyn Garden City, UK (24th Aug 2011) – Cresset and Redx Pharma are pleased to announce that they have signed a major drug discovery collaboration. The collaboration gives Redx Pharma access to Cresset’s publicly available and proprietary computational chemistry technologies for use on their portfolio of drug discovery programs. In addition Cresset will provide consulting services in the area of candidate selection across a broad range of therapeutic areas and targets.

Rob Scoffin, CEO of Cresset said, “Cresset has developed an extensive range of consulting services around the critical areas of library design, compound design, virtual screening and lead optimization. In this case we will initially be focussing our skills on helping Redx with their lead candidate selection process, whilst the collaboration also gives Redx the ability to access our expertise, in a very flexible manner, across the full range of computational Drug Discovery services.”

“Cresset is a valuable partner in our Drug Discovery programs”, commented Dr Neil Murray, CEO of Redx Pharma, “Their deep knowledge of computational chemistry and its application to drug discovery is enabling us to progress multiple projects across a wide range of target classes very quickly and cost-effectively”.

The Redx programs make use of a number of Cresset’s computational chemistry tools. In particular FieldTemplater and FieldAlign are used respectively to provide binding hypotheses and predictions of likely biological similarity for sets of molecules in various lead series.

About Cresset Group Ltd

Cresset develops software for calculating and comparing the molecular Field characteristics of chemical compounds. Field technology uses the surface properties of molecules to evaluate their activities and properties, rather than relying on 2D structure similarity, which enables Cresset’s users to find more interesting, novel and relevant results than other methods. Cresset’s Fields provide a smarter, structure independent way of hit-finding, lead switching and lead optimization in drug discovery and other chemistry-based research projects. Cresset’s field technologies have been successfully applied to a very wide range of target classes, with and without structural information, on over 100 projects for major pharmaceutical and biotechnology companies.

About Redx Pharma Ltd

Redx Pharma’s Redox Switch approach is being used to generate improved versions of existing drugs with patient benefits including greater efficacy, fewer side effects and better ease of use.  The company’s pre-clinical drug pipeline has lead programmes for indications including cardiovascular, antibiotics, influenza and neuropathic pain.  Redx’s IP portfolio includes additional programmes in cancer, diabetes, immune disease and a range of central nervous system (CNS) disorders.  The Redox Switch technology was invented by Redx Pharma founders Dr. Peter Jackson and Dr. Derek Lindsay. Redx forerunner company Bradford Pharma was established in mid-2005, commenced operations at MerseyBio in mid-2007 and became Redx Pharma in late 2010. See: www.redxpharma.com

Cresset August 2011 Newsletter

European User Group Meeting Sept 21 – 22, 2011

Cresset User Group Meeting

There are a limited number of hotel rooms available, so register now to avoid disappointment. 

More information can be found here…


FieldTemplater V3.0: Coming Soon

The upcoming release of FieldTemplater V3.0 provides an improved user experience and massive speed increases.  Due for release on September 1st, this new version provides all of the accuracy you expect of Cresset software, while using remote calcuation resources to dramatically reduce the time for results.

More information can be found here…


ACS National Meeting Denver

Cresset is looking forward to attending the fall 2011 National Meeting and Expo. You can find us at booth 1817, or attend one of the four presentations Cresset will be giving.  This will be a great opportunity to learn about  the latest in Chemistry research, network with other researchers and watch some high quality presentations.

More information can be found here…


SCI – RSC Med Chem Symposium

Two members of the Cresset team will be attending the SCI-RSC Medicinal Chemistry Symposium this Sept 11-14, 2011.  Come find us at booth 8, where you can register for our Design a Molecule contest, ask questions of our medicinal chemistry experts, or register for a free software demo.

More information can be found here…


Design a Molecule: Round 3!

We’re pleased anounce that our third Design a Molecule Contest will begin August 25, 2011.  The rules are simple: register, receive free access to FieldAlign software for the duration of the contest, design the best molecule and win an iPad2!

More information can be found here…

ACS Fall 2011 National Meeting and Exhibition: Air, Space and Water

Cresset is pleased to take part in the American Chemical Society’s 242nd National Meeting & Exhibition this August 28th – September 1st.   Come find us at booth 1817 to learn more about the latest product development, meet the Cresset team, and enter our third Design a Molecule contest for a chance to win an iPad2!  This popular contest give entrants a chance to design a molecule that best matches a specific target using Cresset’s Field Align Software.  Contestants receive free access to the software for the duration of the contest and the designer of the best molecule (as determined by FieldAlign Score) will win an iPad2.  Contest opens August 25th, so come visit us at booth 1817 to enter or click here for details.

The National Meeting program includes  a wide range of excellant presentations, including four lectures from our very own Cresset scientists.   The topic of each presentation is listed below, so make note of the times and locations to attend.

Towards Automated 3D-QSAR:Using Unbiased Alignment of Structures and Non Grid-Based Descriptor Generation on a Series of Human NK3 Inhibitors

Date/Time: Tuesday, August 30, 2011 9AM, Drug Discovery Session

Location: Colorado Convention Centre, Room 302

Presenter: Dr. Rob Scoffin

Abstract: We present details of the development and application of a novel 3D-QSAR approach with the potential to be fully automated. Our method introduces an unbiased molecular alignment step and a non grid-based mechanism for generation of 3D descriptors to avoid some of the key issues inherent with existing approaches. Using an automated molecular alignment step significantly reduces the bias present in existing manual alignments. Descriptors are created at key points on the surface of the ligands under study rather than using a grid, removing key variables (grid spacing and molecular orientation) in 3D QSAR production. Analysis is carried out using PLS, and results are able to be related back to the changes in molecular structure across the series. Validation of the method using literature datasets and application to a prospective novel series of inhibitors of Neurokinin-B (NK-3) receptor inhibitors will be presented.

___________________________________________________________________________________________________________________________

Conformation Searching and the Limits of Conformation Space

Date/Time: Thursday, September 1st, 2011, 9AM, Drug Discover Session

Location: Colorado Convention Center, Room 302

Presenter: Dr. Mark Mackey

Abstract: We present the results of an in-depth assessment of the XedeX conformer searching protocol. XedeX was designed to give conformational diversity within a relatively limited number of conformations, rather than attempting an exhaustive enumeration of conformation space. The algorithm has a number of tuneable parameters including the number of conformers desired, whether a full or partial force field minimisation should be used, the similarity threshold for deciding whether two conformers are different, and whether a torsional threshold for conformer similarity should be included. An extensive analysis of all of these factors on a large database of known bioactive conformations is presented, with results indicating that the optimal conditions for relatively rigid and relatively flexible molecules differ in surprising ways. A fundamental relationship between conformation search performance (as it is usually assessed) and the average number of conformers generated is shown. Finally, the existing literature data sets for assessing conformation search performance are discussed and an improved version provided.

___________________________________________________________________________________________________________________________

Evaluating bioisosteric replacements taking the whole molecule into account

Date/Time: Thursday, September 1st, 2011, 1:30 PM, Drug Discover Session

Location: Colorado Convention Center, Room 302

Presenter: Dr. Mark Mackey

Abstract: Bioisosterism is an important concept in  medicinal chemistry, and the ability to quickly change key parts of a lead molecule without affecting its biological properties is highly desirable. A number of systems for identifying or searching for bioisosteres have been described, but most of these focus on assessing the similarity of the isosteric groups in isolation, ignoring their environment. We describe a new method, FieldStere, which solves this problem. In FieldStere, an active ligand is loaded and a region to be replaced is identified. FieldStere searches a fragment library for replacements that can fit the required vectors. Each proposed replacement is merged into the original ligand, and the entire new molecule’s similarity to the original ligand is assessed using shape and electrostatic properties. The use of product-based scoring allows the steric and electronic influences of the proposed replacement on the rest of the molecule to be assessed as part of the score.  The use of FieldStere in finding new bioisosteres for a number of targets will be presented together with a critique of the current quantitative assessment methods and some proposals for how this may be measured more meaningfully.

Design a Molecule Contest Winner

We are delighted to announce the winner of our second Design a Molecule Contest; congratulations to Chris Swain of Macs in Chemistry!    His excellent design for an anti-malarial molecule has won him a brand new iPad2.  In this contest we asked contestants to design a molecule that mimics a known ligand for Plasmodium falciparum dihydroorotate dehydrogenase as seen in the protein ligand crystal structure 3O8A.  Chris’s design scored very highly in FieldAlign and we are looking at synthesis options for this clever molecular design.

Although the winning molecule’s structure will remain confidential to maintain its IP position, below you will see the fields surrounding the original molecule on the left, and Chris’s design on the right.

Design a Molecule Winner-July6

The Design a Molecule Contests are an excellant way to trial the FieldAlign software for free, hone your design skills and potentially win an iPad2.  Our next contest will be launched shortly before the ACS Fall 2011 National Meeting and Expositionon this August and run until 30th September.   Stop by the Cresset stand at this meeting in Denver, or stay tuned to our newsfeed for details!

FieldAlign 3.0.1 released

Cresset announce the release of FieldAlign 3.0.1. This patch level release of FieldAlign contains improvmenets in the memory footprint and to the internal communications protocol to prevent problems that were observed on Windows XP with the previous version.

This release also incorporates improvements in the molecule table to enhance the selection and display of “favorite” molecules and to introduce the ability to directly edit data present in the table. These minor changes enhance the user experience in line with requests from our customers.

Existing customers should contact their Sales manager for details on how to download and install the latest version. Alternatively a free 30 day evaluations of the latest version is available here.

FieldAlign 3.0.1

Design a Molecule – Hints and Tips: 1

Our current Design a Molecule competiton runs to 8th April. Here I will try to describe how I designed a new molecule using FieldAlign and any tips that I can think of to get you a headstart to the iPad2 that waits for the winner.

First you will need an evaulation or commercial license to FieldAlign and the files for the current competion. This competiton is to design a diverse molecule to mimic the 3-Phosphoinositide-Dependent Kinase-1 inhibitor recently described  by Medina et al. in J. Med. Chem. (DOI: 10.1021/jm101527u). The competition uses the alignment score from FieldAlign as the basis for judging entries so you will need to get as high a score as possible to be able to win. However, molecules with high 2D similarity to the starting point, or with high logP will receive a penalty to their score so that simply changing one atom in the starting point is unlikely to win. To help you we have aligned 200 randomly chosen fragments that you can use to grow or join together into a new molecule. Note that you don’t have to use the fragments to win.

Suggested workflow

  • Open the starting point “Cresset_March2011_starting_point” in FieldAlign
  • Look through the aligned fragments and mark any that you think that you can improve as “Favorites” by pressing the space bar
  • Delete the other fragments to give yourself a small project to work with:
    • Save the project file
    • Add a filter “Fav == false”
    • Highlight all the molecules by clicking on the top molecule, pressing shift and clicking on the bottom molecule
    • Press “Delete”
    • Remove the filter
  • Edit a copy of one (or more) of your favorite fragments, making the changes that you think will give you a better score the save it/them to the project
  • Run menu-> process, use the “Normal” settings
  • Repeat the design and alignment steps until you have the best molecule that you can get; be careful not to copy the reference molecule
  • Highlight you best scoring alignments and export them to an sdf file (File->Export->Selected alignments)
  • Submit your molecules. Note that the maximum file upload size is 70kb.

This is just my suggestion, there are many other ways to get a new molecule. The key thing is to output an aligned molecule in sdf format for uploading to the result page.  Whichever way you use, I wish you good luck.

FieldAlign V3.0 Released – Extends Range of Cloud Computing Apps

Cresset today announced that it has released a major new version of its FieldAlign package. FieldAlign V3.0 is the latest in Cresset’s new generation of “cloud enabled” applications, which support parallel, distributed computing by default. It can be deployed both as a traditional desktop application and as a command-line application distributed onto large computing servers. FieldAlign V3.0 also introduces native support for the Mac for the first time.
FieldAlign is a powerful molecular design and 3D Structure Activity Relationship (SAR) tool which generates biologically relevant molecular comparisons, which can be used to find the root causes of activity or inactivity. FieldAlign helps chemists to gain detailed understanding of the SAR of their lead molecules and to use this to design the best next synthesis.
FieldAlign V3.0 introduces a range of user features that improve productivity and customisability. Its command line interface supports scripting and workflow systems, and is now available on Windows, Linux and Mac platforms. The incorporation of a new molecule table enabling filtering and sorting of lead molecules, using imported data or standard physical properties, such as wcLogP, TPSA, Rule of Five violations. The new molecule editor enables rapid design iterations, while the multi-processor support facilitates faster run times on modern computers. With the option to expand computational power by distributing remote FieldEngines and its enhanced integration with other chemistry applications, more flexible licensing options provide advanced user flexibility.
“FieldAlign V3.0 is now much simpler to deploy throughout a company and easier to use. This gives medicinal chemists access to an intuitive and powerful tool that enables them to accurately evaluate the effect of small design changes before synthesis”, said Tim Cheeseright, Products Director at Cresset.

FieldAlign v 3.0

Enabling Rapid Design and SAR Interpretation

The latest release of FieldAlign brings new functionality that will increase your SAR knowledge and help you design the best next synthesis. FieldAlign has always given you biologically relevant molecular comparisons that can be used to find the root causes of activity or inactivity.

FieldAlign v3.0 makes this easier by enabling sorting or filtering of your molecules using activity, physical properties or other experimental data that you have generated. Combining the filered view with FieldAlign’s excellent molecular alignments gives you a deep understanding of your compounds and the protein that they are targeting.

Using FieldAlign to design the next best synthesis target is now easier than ever. The new molecular editor enables rapid generation of iterative designs, while support for SMILES representations of molecules makes it easy to assess small virtual libraries to determine the best subset to synthesize. Improved support for copy and paste of molecules between FieldAlign, FieldStere and FieldView further simplifies the design process and makes the communication of your recommendations easy.

FieldAlign v3.0 runs on multiple CPU cores, giving you the option to use all the power of your desktop computer, or for bigger problems you can also use Cresset’s unique FieldEngines running on remote resources such as those on an in-house cluster or in the cloud to massively increase the speed of the calculations. Finally, FieldAlign v3.0 is now available as a command line binary enabling deployment in a wide variety of situations and giving ultimate flexibility in molecular alignment and scoring.

The new FieldAlign interface showing CDK2 compounds:

The new molecule spreadsheet in FieldAlign V3.0 showing the clustered alignment view

The new molecular spreadsheet

Rational Drug Design Against GPCRs: Application to CCK2 Antagonists

Structures and Field template d<br /><br /> escribed in the text

Process:

  1. Identify 3 diverse actives for CCK-2 (top left)
  2. Process these actives using FieldTemplater to generate a binding model (
    lower left)
  3. Load 18 diverse actives with known CCK-2 binding affinities (lower right
    ) into FieldAlign together with the result from FieldTemplater
  4. Use FieldAlign to score each of the 18 new molecules against the Field t
    emplate
  5. Plot (top right) FieldAlign scores against measured CCK-2 affinities (Ra
    t stomach pKb), r2=0.75