May 2012 Newsletter

Introducing Forge: Power Computational Suite

We are delighted to announce the launch of Forge, the new computational workbench to understand SAR and the design of new molecules. It brings together all the functionality of FieldAlign and FieldTemplater with new capabilities and new scientific methods in one package.

Forge gives you control and insight into your activity data enabling you to plan the direction of your project with confidence. This new technology uses the shape and electrostatic character of your molecules to create qualitative and quantitative 3D models of activity that are visually stimulating and easy to communicate to your team.


What will Forge do for me?

Forge is a powerful new software suite designed especially for computational chemists. It will help you decipher complex SAR and communicate the results to team members, 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 and lots more. To try it out for yourself, register for a free demo.
Learn more about Forge here…

Forge Training

This FREE webinar is aimed at both medicinal and computational chemists.  It is the ideal opportunity for you to learn all about Forge from our scientific experts. There are a selection of webinar dates to choose from over the coming months so hopefully you’ll find a date to suit you, and once you’ve attended one webinar you can always register to attend another as a refresher and to ask further questions.

Register for a FREE Forge webinar here….


European User Group Meeting

In continuing our series of User Group Meetings we hope you will join us in Cambridge, UK on June 20th – 21st. There will be training sessions that are tailored to the needs of computational and medicinal chemists and will focus on Cresset’s exciting new and existing products. The scientific session includes presentations from Novartis, Heptares, and University of Hatfield amongst others as well as Cresset’s scientific experts.  This popular event always fills up, so ensure you register soon to secures a space.
Check out the program and register for free.

The Design a Molecule Winner is…

Congratulations to Albert J Kooistra, Department of Medicinal Chemistry, VU University Amsterdam who is the winner of our 4th Design a Molecule Competition!  Albert’s molecule won thanks to its combination of simplicity, 2D dissimilarity from the template, fit to the protein pocket and (more subjectively) on its tractability and logP / TPSA profile.  We’d like to thank everyone who entered, and especially congratulate Albert and our other honorable mentions. Enjoy the iPad, Albert!
Read more about the winning molecule here.

What’s new with the website?

You’ve probably noticed that we made some major changes to the names of our products recently. We’re 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 & medicinal chemistry needs and we encourage you to take a look and let us know what you think.

Meet us to find out more

We are exhibiting and running free demos at the following events:

6-8 JuneStructure Based Design, Cambridge, MA.

20-21 JuneCresset European User Group Meeting, Cambridge, UK.

19-22 AugustACS National Exhibition and Meeting, Philadelphia, PA.

26-30 August, EuroQSAR, Vienna, Austria

2-6 September, EFMC-ISMC 22nd International Symposium on Medicinal Chemistry, Berlin, Germany

Check out our other upcoming events.
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Winner of Design a Molecule Competition Spring 2012

Spring’s ‘Design A Molecule Competition’ was Cresset’s fourth and the third to have an anti-malarial flavor. Contestants were asked to design a molecule with a target relevant to antibacterials and anti-fungals.

Cresset was delighted with the response to the competition. The resultant entry molecules were ranked relative to the original bioactive/bound conformer using Cresset’s ‘3D Molecular Field Similarity’ in FieldAlign and then judged on synthetic tractability and drug-likeness. Novelty was also factored into the ranking by imposing a 2D similarity penalty.

Winner: Congratulations to Albert Kooistra (PhD student in the division of Medicinal Chemistry of VU University Amsterdam), the winner of an iPad!

Albert ‘s winning entry won on the grounds of its combination of simplicity, 2D dissimilarity from the template, fit to the protein pocket and (more subjectively) on its tractability and logP / TPSA profile. The design is simple and compact with a nice fit to the pocket. The zwitterionic piperidine fragment provides the necessary twist in the molecule – that is normally induced by ortho-chloro substituents in the parent Triclosan – and potential backbone H-bonding interactions. The addition of this polar fragment also serves to counter the overall high lipophilicity exacerbated by the alkyl thiophene substituent (although maybe too far?).

DAM4_Winner

Image: Winning entry Albert Kooistra, 2D and 3D (modelled in ENR)

In response to hearing about his success winning the competition Albert said: “I really enjoyed competing and using your FieldAlign tool again. Compared to the previous competition (in which I was kindly awarded a 2nd prize) this was a whole new challenge due to the different reference molecule and of course the different target.”

There were many other good entries which were running very close on Albert’s heels, namely: Anthony Nahoum (Strathclyde University) who submitted a couple of nice examples; many imaginative and diverse entries from both Chris Swain (Consultant) and Andrew Lima (4th year student Cardiff University). Well done to all!

Cresset has no commercial interest in exploiting IP from its competitions and so with consent from contestants we are very happy to disclose the winning structures.

Cresset’s Design a Molecule Competition is not only a great way to hone your molecule design skills, but to generate potential leads in the fight against malaria, which is why any IP generated from the competition will be donated to a not-for profit working on this very worthy cause. In preparation for next time you can familiarize yourself with the last competition, or download a demo of our products.

April 2012 Newsletter

Register for Cresset NA User Meeting on May 18

Our North American User Meeting is approaching fast and has only limited spaces. We’ve got free training on our new Forge application, excellent speakers, a new product to show, and we’re still adding to the agenda.

Register now to avoid disappointment


Design Competition Closes April 30

Our fourth design a molecule challenge has again been very popular and now we are giving you just a little longer to get your entries submitted. Already registered – you’ll need a new license file from here. Not registered yet – no problem, you can do it now. We’ve got an introductory video and a full training video to help you get the best molecule that you can.

Design a Molecule and win an iPad, see more.


Sneak Peak at Molecular Forge

We’ve been talking about our new application for a while but it is now very close to release. Along with a new look and lots of new functionality we have a new name – Forge. We hope the capabilities that we’ve introduced will help you knock some sense into your data and help you make something new and shiny!

See Forge in action here.


Meet in Tucson or Elsewhere

We’re attending and exhibiting the National Medicinal Chemistry Symposium in Tucson, AZ, May 20-23 but that is not the only place you can meet us this year. If you missed us at the ACS in San Diego then maybe Philidelphia in August would suit you better? We’re also planning our trip to Vienna for the EuroQSAR as well as polishing the speaker list for our own meeting in June. How about you?

Learn more about Cresset events here.


Teach-Discover-Treat

Cresset is proud to be sponsoring an award under the Teach-Discover-Treat initiative of the COMP division of the ACS. The initiative is aimed at delveloping cutting edge workflows that can be used for teaching and pro-actively in the discovery of active molecules. The initiative takes the form of a competition – put together the best workflow under one of 4 categories and win a trip to the ACS in New Orleans.

Learn more from TDT’s website.


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Getting started with Design-A-Molecule-4

Our popular design competition is well under way but we anxious to geive as much help as we can. Below you will find a short video that introduces the basic worklow. View this if you just want a quick introduction. See our longer Tutorial session if you want something more in depth.

Design a Molecule 4: Sneak Peek

The next Design a Molecule competition begins on March 15th, 2012 and we’re so excited about the next target, we’re giving you a little sneak peek.  Like the last competition, the theme is anti-malarial, but this time we’ve chosen to focus on on a broad spectrum protein target relevant to antibacterials, antifungals and various plasmodium-like human parasites.

The enoyl acyl carrier protein reductase (ENR/FABL/FABI) is involved in fatty acid biosynthesis in bacteria, specifically in the liver stage of plasmodium falciparum life-cycle (PfENR) and more generally in that of Toxoplasmodium Gondi (TgENR).

Triclosan which is a broad spectrum anti-bacterial used in various applications, such as antibacterial soaps and toothpaste, is well established as an inhibitor of ENR’s.  More recently Triclosan has been shown to inhibit the human parasitic forms of plasmodium (PfENR and TgENR) showing some efficacy in mice – although there is controversy over the precise mechanism and involvement of PfENR as the primary target.  A number of X-ray structures are available of ENRs and triclosan analogues (below).

Conversion of Triclosan into a drug has a number of associated challenges:

1. Efficacy – less active sub-optimal at PfENR relative to bacteria

2. Toxicity – poly chlorination is an issue

3. Solubility – too lipophilic logP X TpSA Y – although has to pass through multiple membranes to access target

4. Resistance –  an issue in bacteria

Recent examples of optimisation of Triclosan for Plasmodium ENR have appeared in the literature – some of which may also have potential against resistant bacteria, as in the figure below.

We have created an artificial 3D ligand construct by combining some of the desirable ligand complex examples from the PDB in order to address poly-chlorination issues. It should be noted that this is simply a ‘virtual ligand template’, representing accessible ligand –protein interface within PfENR, which we hypothesise to be useful for scoring potential designs against – and is not a known active.

The challenge in this competition is therefore to design a ligand that addresses the issues above as much as possible. The winning entry will have the highest score against this construct whilst having the lowest 2D similarity. The winner will also be judged on synthetic tractability and the extent to which the design addresses the issues described above (1-4).

Competition Details

The competition runs March 15th – April 20th and we’ll give you more detailed instructions along with the 3D molecule file when registration opens.  If you’re new to Design a Molecule, here’s how it works:

1. Register for the competition

2. We’ll give you a target molecule and free licenses to FieldAlign and FieldView

3. Design the very best molecule

4. Submit the molecule to us

5.  Win an iPad2 (Well, only if you really designed the very best molecule in the bunch)

Feel free to contact us with questions about our target selection, the competition or using Cresset software for molecule Design.

Update March 15: The competition is now open, register here and see the instructions here.

October 2011 Newsletter

Announcing the Fall 2011 Design a Molecule Competition Winner!

Designa Molecule Competition Winner
This competition was our most popular thus far and the entries were so excellent we couldn’t chose just one.  You can read about the winners (and a few very honourable mentions!) here.

FieldView: Tips and Tricks Part 1

FieldView is our extremely popular 3D  molecular viewer and editor.  In order to help you make the most of this software, we’ve created a quick guide full of tips and tricks for using the FieldView viewer.  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…


FieldStere V3.0: Sneak Peak

The newest version of FieldStere will be released in a few short weeks, and we’re very pleased with the improvements.  This release includes new features that enable the optimization of one series against another and the growing of fragments.  These features coupled our improved user interface make this release something to get excited about.

Find out more about FieldStere 3.0 here…

Cresset: 25 Years of Fields

Cresset has officially been in business for 10 years, but we’ve been working on fieldsfor much longer, in fact, it’s been 25 years!   This humorous presentation chronicles the lessons we’ve learned in the past quarter century, including ‘How NOT to write a paper’ and ‘Virtual Screening is really hard.’

Watch this hilarious presentation here…

Cresset UGM Presentations

We are absolutely delighted with the success of our UGM and thoroughly enjoyed meeting many of you face to face.  If you were unable to join us at the meeting in September, you can still take a look at some of the work that was presented online. And stay tuned for information about our next UGM, available soon!

Take a look at the presentations here..
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Design a Molecule Competition Fall 2011: Winner Announced

This Fall’s ‘Design A Molecule Competition’ was Cresset’s third and the second to have an Anti-Malarial flavor.  Contestants were asked to  design a molecule which reconnected the fragments of a Farnesyl Transferase inhibitor from the PDB and to effectively replace the core of the ligand with a new framework.  The choice of ligand and target was made with some thought to balance the ease and likely interest in the task with relevance in the field, without getting drawn too deeply into drug the discovery process and its many, many issues.

The very entertaining storm which ensued illustrated perfectly the potentially embroiling diversity of opinion in the drug discovery arena.  Despite this and initial reservations about the difficulty of the challenge, Cresset was delighted with the response to the competition.  The resultant entry molecules were ranked relative to the original bioactive/bound conformer using Cresset’s ‘3D Molecular Field Similarity’ in FieldAlign and then judged on synthetic tractability and drug-likeness. Novelty was also factored into the ranking by imposing a 2D similarity penalty.

Cresset has no commercial interest in exploiting IP from its competitions and so with consent from contestants we are very happy to disclose the winning structures.

Winner: Congratulations to Peter Ertl of Novartis, the winner of a brand new tablet!

Peter’s design was very elegant, compact, with far less conformational flexibility and high field and shape match, relative to the starting inhibitor. Peter cleverly used the triazole replacement to capture the fields provided by both imidazole moieties in the reference. In the complex these are involved in metal ion and H-bond acceptor interactions from tryptophan/tyrosine.  The aryl ether moiety would provide a suitable chemical handle for driving selectivity specifically towards the malarial target.  Peter’s design is reasonably drug-like, with a  low mwt 400, logP 4.6, TPSA 80 and synthetically tractable.

A very close second place result goes to Albert Kooistra (PhD student in the division of Medicinal Chemistry of VU University Amsterdam).  Albert’s design was so near to winning that we have awarded him with a second prize: An Amazon Kindle.  Well done!

Albert took a more literal approach, maintaining all the original fragments, to produce high field and shape match, although invoked a higher 2D similarity penalty than Peter. Albert engineered a very nice imidazol-sulphonamide bioisostere which maintains H-bonding interactions to Arg in the complex. These interactions are not as well served as by Peter’s design.  Albert’s design is also reasonably drug-like mwt 477, logP 3.9, TPSA 98 but is arguably less synthetically tractable or amenable to further synthetic exploration.


Finally, in the image below, you can see the molecules in the context of protein.


There were several other very nice results worthy of an honourable mention:

Andy Knox (Trinity College Dublin), Brad Teegarden (Consultant), and Sandeep Sundriyal (Texas A&M Health Science Center) all submitted cyano indole and aza-indole starting points, which scored highly and had great tractability.  And finally, a very worthy mention for Matt Baumgartner (University of Pittsburgh) who submitted all of his results featuring single step syntheses, showing a commendable appreciation of the issue of cost of goods and synthetic tractability in the Malarial field.

Congratulations to all of our winners and thank you to the rest of our entrants.  We will run this competition again, please watch for details.

September Design a Molecule

Detailed steps on how to enter the design competiton are presented below. Or watch the video version.

  1. Enter the competition to get everything you need
  2. Download the zip file using the link in the email that you get sent
  3. Unzip the downloaded file and follow the instructions in the readme document
  4. Install FieldAlign and FieldView from the “Software” folder
  5. In the “Competition” folder Double click the left mouse button on the FieldAlign project: “START_HERE_Sep11.fpj” to open this file in FieldAlign.
  6. Note two 2d molecules present in the molecule table: the reference (yellow block background) and four disconnected fragments (query)
  7. Select the query molecule in the table with the left mouse button (should turn to a blue background).
  8. Right click and select “Edit a copy of the selected molecule” to open the Molecule editor.
  9. Hold LMB on background and move mouse to rotate view.
  10. Edit (add atom) by dragging and holding LMB from a fragment. Ctrl-Z will undo. Hold Ctrl will toggle selection mode. Delete will delete selected atoms.
  11. Repeat to connect the fragments and design the replacement core using whichever atoms you wish: Select from the left hand atom menu; double click on a bond to toggle bonding.
  12. Minimise core only: Using the selection tool highlight the core (cyan) click minimise.
  13. Once you are happy: Save to exit the editor.
  14. To align the new molecule query and calculate a similarlty score: Click process (calculate icon) in the top menu.
  15. Repeat the process to refine the design or start again from the fragments.
  16. Once you have a winning design, export the molecule: Select the molecule to export by left clicking on it in the table then use File menu -> Export -> Export selected molecule
  17. Save the molecule to an sdf file
  18. Upload the molecule to enter or send it to support@cresset-group.com

Video tips for September Design a Molecule

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…