Review of Cresset European User Group Meeting June 2012

Our scientific programme reflected the wide range of scientific fields involved in drug discovery and the depth of breadth of scientific knowledge that goes into developing software for in silico research. The talks ranged from the force fields involved in protein-protein interactions to the use of NMR technology to understand drug metabolites. Below is a review of each presentation. If you would like further details of any presentation please contact us.

Dr Jon Mason of Heptares opened the day’s scientific talks with an informative overview of his work on the energetics of water networks in proteins. Having worked in this field for over 25 years, he has reached a point where he has found that the computational mapping of water energetics in a protein target has a high correlation with druggable binding sites for targets, or at least with ligandable targets.

Dr Mark Mackey, Cresset’s Chief Scientific Officer gave an overview of the new science that Cresset has been working on, including how conformations are generated, new sampling methodology for 3D QSAR, advances in fragment growing technology with the option to merge results from multiple ligands, and finally an updated force field, FF3 which refines and improves Cresset’s existing XED force field. He also introduced forgeV10, Cresset’s new 3D QSAR environment.
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Dr Peter Ertl, Director of Cheminformatics at Novartis shared his Intelligent Automated DEsign (IADE) method for bioisosteric design. His automated fragment replacement system firstly identifies bioisosteric fragments for a given compound and replaces them iteratively to generate several hundred analogs. These are converted to 3D structures using CORINA. Reasonable conformations are generated using Cresset software and the conformation most similar to the target is identified using FieldAlign. He used this method to design the winning molecule in Cresset’s ‘Design a Molecule’ competition in October 2011.

Dr Andy Vinter, Cresset’s Chairman updated us on how he has used the XED force field to normalise proteins and gain insights into the actions of agonists and antagonists. He reminded us that atomic charges do not sit on the nucleus, as some force fields approximate, but rather the real electrostatic charge varies close to the atom, as reflected in Cresset’s unique FF3 force field.
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Drug repositioning is an increasingly popular area of drug discovery. The increasing costs of R&D and decreasing return on investment has lead many companies to focus on finding new opportunities based on existing drugs and their templates. Dr Alan Rothaul gave an overview of structure and non-structure based methods of repositioning and showed how structure based re-profiling through fragment swapping can feed into new compound discovery. He pointed out that new intellectual property has to be established and that this is often determined through reformulation.
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Dr Ute Gerhard of the University of Hertfordshire demonstrated how the power of NMR and mass spectrometry analysis are used to determine the structure and concentration of drug metabolites. The detection limits for state of the art NMR are now where mass spectrometry was ten years ago. NMR can be used to successfully identify potentially toxic metabolites so that only good quality drug candidates are progressed through the discovery process.
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Optibrium and Cresset recently announced a collaboration to combine the power of Optibrium’s StarDrop with Cresset’s FieldAlign. Dr Matthew Segall of Optibrium gave an overview of multiple parameter optimization (MPO) for drug discovery, as delivered in StarDrop. Drug discovery demands that chemists make confident decisions based on complex multi-dimensional data. The challenge is to optimize the vast quantities of data available, while making allowances for data accuracy and weighting.
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Dr Ronnie Palin of Redx Pharma gave an overview of their approach to drug discovery by discussing novel lead identification using similarity scores. He explained the best starting point is existing drugs since they are known to hit the target and the majority of the optimisation has been done. Their Redox Switch technology is used to change the chemical structure, then Cresset FieldAlign was used to rank the Redox Switch ideas to give the rapid identification of hits in unexploited IP space. Based on this work they have filed patents in multiple therapeutic areas. He gave the example of changing carboxylic acids while retaining activity. Their anti-viral project started with the known anti-flu compounds zanamivir, oseltamivir and peramivir. Their chemists generated ideas to replace the carboxylic function, then Cresset data was used to score the results and the best results were optimized. The found good correlation between the predicted binding and the inhibition of neuraminidase.
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Dr Raj Gosain of the University of Southampton told us about two recent projects that his students have carried out using Cresset software to virtually screen compounds of interest against the ZINC database of screening compounds. In the first case a student started from an unusual squaramide structure, which when it was run through the database identified a new compound that whilst having lower activity was actually a more selective hit. Dr Gosain pointed out that they could not have arrived at this compound with any method other than Cresset software. The second example was looking for an inhibitor of the anthrax lethal factor. Starting from a compound with little potential IP due to existing patents they were able to find a tractable starting point for medicinal chemistry, which had novel structure and was clear of existing IP.

This stimulating mix of talks covered an engaging mix of disciplines including pharmacology, medicinal chemistry and computational chemistry. Dr Rob Scoffin, CEO of Cresset summed up the day by reviewing how Cresset has grown and changed over the last year: “Cresset’s customer base is expanding, there has been rebranding with new product names and organizations. However, our core focus remains the same: to provide the best science with the best customer support”.

Fields at Warp Speed

There is a revolution happening in high performance computing. Calculations that once took hours or days to run can now be done in just minutes. The secret? Graphics Processing Units (GPUs), commonly called “graphics cards”. Graphics cards are no longer limited to just moving triangles around on screen: they are now phenomenally powerful parallel computers in their own right. They can only do a limited subset of tasks, but do them at lightning speed.

Cresset is working to bring this exciting revolution to all our customers. We have have a collaboration with the high performance computing group at the University of Bristol, UK that will implement new GPU based algorithms within the core of our field technology. Our collaboration takes the form of a Knowledge Transfer Partnership (KTP) scheme from the UK government which provides a way to transfer knowledge held in academia out into industry. As part of this we have recruited Simon Krige, a GPU programming expert, to the Cresset team. Simon is working closely with Prof. Simon McIntosh-Smith at Bristol whose group is one of the world leaders in high-performance parallel computing, and is helping to bring their expertise into Cresset.

Simon (Krige) has made great advances in the few months that he has been with us. He has rewritten large sections of the core field similarity algorithm in openCL, a framework that will execute on either regular CPUs or GPUs. The beauty of this system is that the code runs wherever it can go fastest, on your CPU if you do not have a fast GPU or on the GPU if you do. In this way speed increases should be available for desktop as well as cluster based applications.

So far the numbers are impressive with speed increases of 40x being observed in a virtual screening environment on standard graphics hardware. Simon is eager to point out that this may not be maintained when we are in a desktop environment where the workload is more sporadic. However there is plenty of optimization of the code still to do and so speeds could go up as well as down.

As part of our development schedule we are looking for partners to start alpha testing in the next couple of months. If you are interested in collaborating with us on this please email us.

Dr. Andy Vinter: A Career Tribute at MGMS

Cresset’s founder, Dr. Jeremy Gilbert Vinter (known to all simply as Andy) has had a truly remarkable career and all of us at Cresset are delighted that the MGMS  (Molecular Graphics and Modelling Society) has chosen to honour his hard work with a meeting this September 19th -21st.   During his career, Andy has published over 50 scientific papers in peer-reviewed journals, contributed to 7 books and co-edited 1.  He has held visiting professorships at the universities of Sussex, Brunel, KCL, UCL and Utrecht, and been a faculty member at Cambridge. He has served on 9 government research council committees and 3 peer-reviewed journal editorial boards.

However, beyond such impressive career statistics lies a beloved colleague with a great sense of humour and an impressive insight into the future of drug discovery.  And so we present to you: 8 Questions with Andy Vinter:

1. What was your first job?

Sucking urine up a mouth pipette for salicylate trials by the uncouth toxicology department at Beecham’s Labs Mansion in Surrey (1964).

(Toxicologists are always naughty… one once told his American bosses at SKF that he had “crossed the ‘Ts’, dotted the ’Is’ and licked the ‘Rs’” for them   –  he got the sack!)

2. What is your career highlight?

Apart from being honoured in two weeks, there was the day the XED force field worked for me (1994), the day Wellcome gave me a grant to start Cresset (2000) and the day I was told I had won the Ramsey Medal at UCL for best postgrad (1973).  All of them a great surprise.

3. Of the many projects you have worked on, which are you most proud of?

Many (over 100 now) I know little of the outcome and any one could have been life-changing for the client but we will never know.  The most successful to my knowledge was the Cortisol/Cortisone 11betaHSD project in 2003 which is still going on- but there was a sad end for Cresset because we were cut out (for obvious reasons) very early on…  You can’t hope to win against the Wellcome Trust!! 

I think the Divergence Projects have been most exciting.  Tim [Cheeseright, Cresset’s Products Director] did the original work that has probably contributed most to the success and eventual take-over by Monsanto.  But hear what Matt [Dimmic, of Monsanto] has to say at the Cresset User Group Meeting, pretty impressive!!

4. Who has been your biggest influence professionally?

Jim Black –undoubtedly.  He encouraged me non-stop from 1974 to his death in 2010 when everyone else thought I was off my trolley.  My lecture at the MGMS ‘do’ is entirely based on his influence and interests.  He was magic.  I have never met a match for his insights and enthusiasm. (Look him up on wikipedia – Prof Sir James Black OM FRS)

5. Where do you see drug discovery technology moving in the future?

A long question!!  Where it will go and where it should go are, I suspect, very different. The understanding of biological processes is primitive beyond belief and to think that attacking one particular target will lead to the expected clinical outcome is wishful thinking (as has been proved time and time again). 

For Big Pharma, where it will go will depend on two things:

1) the money available for basic research, which is diminishing as their pipelines drain because of failed methods, escalating costs and FDA restrictions.

2) the stupid uptake of the latest scientific wow- whether it works or not – because that is what will turn managers on. Drug discovery money for academics dominates over basic science grants these days (trendy). This is  leading to a lot of contrived research applications that cannot be properly completed or understood commercially.   So- although Pharma will turn away from basic research and use academia to fill the gap, the fusion between the two will not be efficient enough to sustain good pipelines.

What should be done is to revert to the old thinking of serial drug development  – doing some chemistry, waiting for a biological result and doing some more chemistry based on that info.  Parallel methods have been the undoing of Pharma since 1990.  We need to set up dedicated teams (from academia and industry) that can use the amazing new technologies;  microfluidic chemistry for economy and speed/ cell-based biology to account for complex interrelated processes/ Xray and nmr spectroscopy for structure/ integration of validated computational methodology, all over-lorded in a focussed way to maintain discipline and target validation (which means getting it into man as early as possible) by experienced and visionary scientists who have the teeth to keep the sceptics, cynics, accountants and idiots from interfering.  This is the way to go….you asked!!     

6. What are your thoughts on the MGMS meeting held in your honour?

Tickled – nay overwhelmed, embarrassed, not quite sure why but very grateful and a bit apprehensive…

7. What is the most unusual experience you’ve ever had working in a Chemistry lab?

Maybridge Chemical Company Ltd, Cornwall – 1968- before I came up to London to do a PhD.  There were only four of us in individual rooms in a tiny lab on the edge of Bodmin Moor, isolated from the rest of humanity, making what we liked with little care for Health and Safety.  During an unusually snowy winter in North Cornwall we  kept warm by keeping on our electric hob heaters.  It happened one day that I mishandled a conical flask full of ether and the solvent dribbled all over my right arm making it feel very cold as it hastily evaporated.  You may guess what happened.  As the vapour reached the heater my arm didn’t stay cold for long and suddenly it was spectacularly ablaze!  Fire extinguishers- what were they?  Not knowing what to do, I shouted for Steve, the senior chemist.  Without hesitation, he bundled me through the outside door and rolled me in the snow to put me out.  Although I was in bandages for three weeks,  I could now be one-armed if it hadn’t been for dear old Steve (whose surname I have forgotten) – Thanks mate- wherever you are…

8. What would you have for your last meal on earth?

A beef roast with potatoes cooked in goose fat with English mustard followed by ice cream and a bottle of Chateau Margaux 1985.  On the other hand, a cheese sandwich would do – and would I be hungry anyway! 

Like Andy as much as we do?  Come meet him at the MGMS and the Cresset User Group Meeting.


Field-Focused Library Design

Article published in Drug Discovery and Development:

When designing libraries against specific targets, a wide range of activities—therapeutic, off-target, and toxicity—must be predicted. Experience has shown that a compound’s biological activity cannot be predicted solely by its 2D structure and we need to use a more detailed description of the molecule. At its most basic level, activity is determined by the interactions of the molecular fields (surfaces) of the target protein with those of the ligand in their respective binding conformations.
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