Cresset seeks partners for beta testing of groundbreaking new Activity Miner module for rapid 3D SAR interpretation

Welwyn Garden City – 2 July 2013 – At Field Based Chemistry Europe, Dr Tim Cheeseright presented a pre-release of Cresset’s new Activity Miner module.  The groundbreaking new science in Activity Miner helps researchers optimize their leads by identifying the key 3D structural and electrostatic changes that impact molecular activity.

Activity Miner explores the structure activity landscape of a set of molecules. For each pair of molecules, the difference between them in electrostatics, shape and structure is compared to the difference in activity. A small change in structure or electrostatics that results in a large change in activity is known as an activity cliff.  Conversely, large structural changes resulting in little or no change in activity indicate bioisosteres.  In each case, the comparison indicates an area of interest that merits further research.

Activity Miner uses Cresset’s molecular fields so that 3D electrostatic and shape similarities can be analyzed as well as 2D structural activity.  This makes it meaningful to compare pairs of structurally diverse compounds and gives a more realistic insight into activity relationships.

“Based on internal validation experiments, we believe Activity Miner is a powerful tool for guiding lead optimization and mining the SAR to rapidly generate new and more active structures for experimental evaluation,” says Dr Mark Mackey, Cresset’s CSO.  “Activity Miner’s intuitive visualization makes it easy to identify interesting areas of a dataset.  The relationships between molecules can be displayed as a color coded disparity matrix, a table view, a cluster view or the innovative activity view (below).”

Activity View

Browsing through the ‘Activity view’ is a quick way to find the key features of the SAR in the dataset. 

“Activity cliffs and matched molecular pairs have received a great deal of recent attention in the literature,” says Dr Tim Cheeseright, Director of Products at Cresset.  “So far as we are aware, Activity Miner is the first commercially available tool that enables researchers to use 3D and 2D activity cliffs to mine structure activity relationships in an intelligent and intuitive way.”

Activity Miner is available for beta testing over the summer.  The full version will be available in the next release of Cresset’s Forge and TorchContact us to take part in the trial.

More information about the features in Activity Miner.

Victrix CMCC chooses Cresset’s software for consulting projects to give insight into molecular activity

Welwyn Garden City, UK – 27 June 2013 – Cresset, innovative provider of chemistry software and services, announces that under a new agreement, Victrix CMCC will use Cresset’s software for their computational chemistry consulting projects. Cresset’s Spark, Forge and Torch software will help Victrix clients carry out structure-based drug design projects and to build predictive 3D SAR models for lead identification.

“Victrix is very pleased to be able to offer our clients access to Cresset’s software,” says Dr Adam Kallel, CSO of Victrix.  “Cresset’s field based software significantly expands our ability to help clients with programmes that have little or no structural information.”

Dr Kallel adds, “I have been a believer in field based methodology since I began work in the pharmaceutical industry and I was an early adopter of the Cresset technology.  I believe the XED force field that underlies Cresset’s software provides the ability to model molecules and their molecular fields in a way that is as close to high level quantum mechanics as possible, giving valuable insights into structure reactivity relationships. I strongly recommend its use and am very pleased to provide this functionality to Victrix clients.”

“We are delighted that Victrix has chosen to use Cresset’s software for their consulting projects,” says Dr Robert Scoffin, CEO of Cresset.  “Our field based approach of using 3D electrostatics and shape to understand molecular function is particularly valuable when there is no information available about the protein target.  We look forward to Victrix clients experiencing the difference our software will make to their research.”

February 2013 Newsletter

Newsletter 2013, Is Chocolate Druggable?
This month Dr Rae Lawrence takes her inspiration from shop shelves groaning with early Easter eggs as she applies desktop virtual screening to theobromine, that magic substance found in her favorite food. Read on to find the answer to her question: Is chocolate druggable?

New Release of XedTools

Cresset’s popular XedTools package has been updated to include the next generation of our XED force field plus some exciting new features:

  • easily minimize ligands within a protein active site using XedMin
  • improved performance of our conformation hunter XedeX
  • create 3D representations of molecules from smiles strings or 2D sdf files with XedConvert.

Read more.  Register here to get your free 12 month license to XedMin and XedConvert or 1 month evaluation of XedeX.

Field Based Chemistry 2013 – Register Now

Registration is now open for attendance at Cresset’s user group meetings:

The meetings are made available at no cost to delegates and include: scientific program; hands-on software workshop; the opportunity to network with the Cresset team and other delegates.

There is still the opportunity to speak or present a poster at the Europe event. Abstracts should be submitted by March 15th.

Using Scaffold Hopping to Search Nearby Chemical Space

Continuing his series of blogs on how computational chemistry can help to find new drugs from old, Dr Rob Scoffin, CEO of Cresset, examines scaffold hopping.  Making structural changes to an existing drug compound enables you to search the nearby chemical space.  The aim is to find a new compound with similar chemistry that retains the desired activity and also shows some improvement.  Read the article.

Great Communication Makes a Great Consulting Project

It’s fair to say that good communication can make or break almost any scientific project, but it is particularly important when working in a consulting model. Dr Martin Slater, Director of Consulting at Cresset, shares how vital it is to have good communication between medicinal chemists and computational chemists. Read more.

Is Chocolate Druggable? Using Theobromine for Desktop Virtual Screening

Dr Rae Lawrence, Cresset’s Technical Sales Director for North America, is a self confessed chocoholic.  For this blog she has spent some quality time with her favorite food, investigating the chemistry of the compounds that produce the delicious taste, desirable effects, and even the addictiveness claimed by some.  With Valentine’s Day just behind us and Easter around the corner, there’s no better time to think about this wonderful topic!

Dark chocolate has long been reputed to be a healthy dietary addition.  It is claimed to be a mood enhancer, cough suppressant, and a key nutritional supplement for cardiovascular health.

There are a few hundred pharmacologically active compounds in chocolate, including, but not limited to:

  • Theobromine and caffeine (CNS stimulants);
  • Salsolinol  – dopaminergically active, and possibly responsible for chocoholism1;
  • Anandamide  – an endogenous cannabinoid neurotransmitter;
  • Phenylethylamine – the alleged ‘love chemical’, another endogenous neutrotransmitter.

Even within this short list of components, it’s easy to see that given their CNS activity, chocolate is indeed mood-altering.

For this discussion, I will focus on theobromine, which is the component responsible for many of chocolate’s pharmacological effects and its bitter taste.  Theobromine is part of the methylxanthine class of compounds and has a similar structure to caffeine.  Pharmacologically, theobromine is a known antagonist of both Adenosine A1 and A2a receptors, as well as an inhibitor of cAMP-specific-3’,5’-cyclic phosphodiesterase 4B (PDE4B).2

This month I will use the virtual screening capabilities of forgeV10 to compare the biological properties of theobromine to a database of known pharmaceutically active compounds. For more information or a demonstration of how we compare molecules in field space, please contact or read our 2006 paper, which summarizes the technology and algorithms3.

Scouring the Literature and Google

When I started researching the pharmacology of chocolate, I discovered that theobromine appears in nefarious message boards4 suggesting that it can be used for a legal high when taken as an extract.  Reading a little further down the board, one user noted that theobromine itself didn’t really give the desired opiate numbing effect (considering its similarity to caffeine, no surprise there).  However, when they took kratom5 with it, the effects of kratom were more pronounced.

My interest was piqued by this, so I googled ‘theobromine opiate’ and while digging through the results, found a couple of peer-reviewed articles where it was reported that a shot of adenosine during anesthesia and surgery reduces the amount of opioid pain-killers required for post-operative recovery6.  Pharmacologically, theobromine binds to the A1 and A2a receptors, and thus, it is plausible that theobromine may have a similar, albeit, less pronounced effect – and given the anecdotal evidence provided by law-bending netizens and their search for inexpensive, legal highs, we might be on to something!

Theobromine and Adenosine, Adenine and N9-methyladeninea

Figure 1: Theobromine and Adenosine, Adenine and a N9-methyladenine.  Blue field points are negative, red field points are positive, yellow field points denote shape, and orange field points denote hydrophobicity.

Notice the lower similarity score when comparing adenosine to theobromine.  The decreased similarity is a result of the molecules’ different sizes.  When we look at the similarity scores for Adenine and the modified N9-methyladenine, the scores suggest higher similarity for the fragments.  This suggests that theobromine is likely accessing the same part of the Adenosine Receptors’ binding site as the purine piece of the natural ligand, adenosine.

Theobromine’s Anti-Tussive Properties

In a recent publication from National Heart and Lung Institute (London)7, it was demonstrated that theobromine has significant anti-tussive (cough suppressing) properties via inhibiting action potentials in the vagus nerve.  Theobromine’s activity was compared against codeine, which is the gold standard in cough suppression, and was found to be as good as codeine, and without the adverse side effects or addiction risk.  BC1036 (theobromine) is currently being developed by SEEK and Pernix Therapeutics and is has just begun Phase III trials.

Theobromine with codeine

Figure 2: Theobromine and codeine compared in field point space.  The low similarity score leads us to hypothesize that these molecules are likely to be binding to different receptors or alternate areas of the same receptor responsible for relaxation of the vagus nerve.

Desktop Virtual Screening

With the plethora of information about the pharmacology of chocolate, I thought it would be interesting to run a desktop virtual screen of theobromine against the Drug Bank’s databases8 of approved drugs using forgeV10.  Since theobromine is a fairly rigid flat molecule, we don’t need to be concerned with elucidating a binding mode.

Examination of the PDB structure9 3RFM, in which caffeine is bound in the A2a receptor, showed the binding conformation of caffeine to be flat and rigid, comparable to the theobromine conformation used as a starting point reference for the experiments outlined in this article.

Before conducting any experiments, the Drug Bank databases were visually inspected and curated (i.e., removal of counter ions, waters, etc.), leaving only the drug structure.  The structures within the approved database ranged from quite small to quite large and floppy, so in hindsight, I should have run only their small molecule database – it would have been far less stress on my poor laptop.

When aligning molecules under Normal settings within forgeV10 (or torchV10), it is important to note that the molecules are not aligned simply on structure, but on their field point patterns – it’s well reported that even when the 2D structural similarity is low, it’s possible that two compounds can have similar “personalities” (i.e., shape, hydrophobicity, and charge distribution)3.


In the approved drugs database, the top hits were as expected – theobromine (0.998) and caffeine (0.942).

Theobromine with caffeine

Figure 3: Comparing Theobromine and Caffeine.

The next best scoring results were a series of PDE inhibitors that result in vasodilation and bronchodilation, and are used in treatment for asthma and COPD patients.  These are as expected, as the xanthine moiety is conserved through this set of compounds.

Theobromine and PDE inhibitors

Figure 4:  Comparing Theobromine to PDE inhibitors used for vasodilation and bronchiodilation for the treatment of asthma and COPD.

A surprising set of hits were lower scoring (0.729-0.799), but don’t share the xanthine scaffold.

Lower scoring comparisons with theobromine

Figure 5: Lower scoring comparisons for Theobromine.  The similarity scores aren’t fantastic, but they are still worth a look.

Azetazolamide is carbonic anhydrase inhibitor used as an anti-convulsant and to relieve intracranial hypertension; Pyridoxal and Pyridoxine are forms of Vitamin B6; Menadione is Vitamin K3;  Metharbital is an anti-convulsant barbiturate with similar properties to phenobarbital; Stavudine is a nucleoside analog reverse transcriptase inhibitor (NARTI) with some activity against HIV; and Oxitriptan is a chemical precursor to serontonin and melatonin, and is sold as a nutritional supplement for anti-depression and insomnia.

It is noteworthy that if we look at the rotamers of the hydroxyl groups of pyridoxal and pyridoxine, the alignment score decreases.

Could chocolate be a vitamin/anti-depressant truth-serum that helps with high blood pressure and HIV?  Seems like a snake-oil claim, like those single cures sold in the late 19th century that simultaneously cured diarrhea and constipation!

These lower scoring results are on the borderline of what I would consider worth a peek, but at the same time, it’s interesting to note that there are some similarities to theobromine – perhaps a re-profiling study is in order? (See Rob Scoffin’s recent posts for more information about teaching old drugs new tricks).


In cases presented above and examining the hits from the desktop virtual screens, it’s clear that the pharmacological activity of theobromine is both exceptional and diverse.  Being a small molecule, it’s no surprise that this fragment can access binding sites in a variety of targets to achieve medicinal effects!

To answer the question of whether chocolate is druggable, given the success of the theobromine anti-tussive drug that is currently in Phase III trials, I’d have to say “yes”.  That being said, I don’t think we have enough evidence here to support confiscating Cadbury Easter eggs from your children next month with the explanation that they contain “drugs”…

Until next month,


References and Citations

  1. J. Ethnopharmacol., 2000, 73, 1530159; Physiol. Behav., 2011, 104 (5), 816-822.
  3. J. Chem. Inf. Model., 2006, 46(2), 665-676.
  5. Kratom is a traditional Thai medicine used to treat chronic pain and opioid dependence. It is not currently regulated in the USA or Europe.
  6. Eur. J. Pharmacology, 1998, 347 (1), 1-11.; Anesthesia & Analgesia, 2007, 105 (2), 489-494.; Korean J. Pain, 2011, 24 (1), 7-12.
  7. The FASEB Journal, 2005, 19 (3), 231-233.
  8. DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, Neveu V, Djoumbou Y, Eisner R, Guo AC, Wishart DS. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. 
PMID: 21059682;  DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. 
PMID: 18048412;  DrugBank: a comprehensive resource for in silico drug discovery and exploration. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72. 
PMID: 16381955.

Additional Notes

Safety First – Theobromine is extremely toxic to dogs (LD50 – 300 mg/kg). Please be careful to keep your chocolate treats (especially dark chocolate) out of reach of pets.  Chocolate + Dog = Expensive visit to the vet

Adenosine A1 Antagonism

The Adenosine A1 receptor is a GCPR receptor for which adenosine is the endogenous ligand, and has been found to be involved in sleep promotion by inhibiting cholinergic receptors in the basal forebrain, and also present in the vascular system’s smooth muscle to regulate myocardial oxygen consumption and blood flow through the heart muscle.

Adenosine A2a Antagonism

The Adenosine A2a receptor is a GCPR receptor (PDB:3EML) with adenosine as the endogenous ligand.  A2a regulates myocardial oxygen consumption by vasodilating coronary arties, which may result in hypotension (decreased blood pressure).  In the brain, it regulates the release of neurotransmitters glutamate and dopamine, and has been indicated as a potential target for treating Parkinson’s Disease, addiction, and mood disorders.

The Changing Face of Computational Chemistry

Chemistry software for drug discovery is becoming increasingly polarised into expert tools for computational chemists and 3D desktop modelling tools to support the work of medicinal chemists.

Day to day desktop tools enhance the work flow of medicinal chemists, while companies are increasingly choosing to outsource computational chemistry to consultants as a cost effective way of accessing expertise in a timely fashion.

Read the full article by Dr Martin Slater, Cresset’s Director of Consulting, on Page 38 of the Feb/Mar 2013 issue of Scientific Computing World.

Switching Series

When researchers find their promising lead series facing IP issues, they are faced with a tough decision. Do they change series—possibly to a candidate that doesn’t show the same level of activity against the target—or do they spend a great deal of time and money screening the totality of the corporate database for a new prospect? In this situation, scaffold hopping and virtual screening are effective and efficient ways to identify a new series to move the project forward.

Read the full article by Martin Slater and Katriona Scoffin in Drug Discovery and Development Magazine.

The Advantages of Outsourcing Computational Chemistry

According to Martin Slater, Director of Consulting at Cresset Biomolecular Discovery, there are two main factors driving the current increasing trend to outsource computational chemistry: first, a trend to outsource across the discovery spectrum.  “The increasing fragmentation of the drug discovery business has brought an increase in companies that can move quickly to offer tailored research, often through the use of on demand services from consultants”. The second factor is that big pharma are seeking to reduce their R&D costs as many key patents are due to expire over the coming years.

This article appears in the January/February 2013 edition of sp2 Inter-Active magazine: The Advantages of Outsourcing Computational Chemistry (Part 2).

The first part of this article, The Advantages of Outsourcing Computational Chemistry (Part 1), appeared in the November/December 2012 issue of sp2 Inter-Active.