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Cambridge MedChem Consulting

Drug Transporters

An interesting meeting next month, a few spaces left apparently.

Drug Transporters

More details and application form here

Drug versus Metabolite similarity

A recent paper from Douglas Kell et al DOI has provoked much discussion, especially since it was highlighted on In the Pipeline. The authors suggest that similarity to a human metabolite may be a useful as an indication of how “drug like” a molecule might be.

We exploit the recent availability of a community reconstruction of the human metabolic network (‘Recon2’) to study how close in structural terms are marketed drugs to the nearest known metabolite(s) that Recon2 contains. While other encodings using different kinds of chemical fingerprints give greater differences, we find using the 166 Public MDL Molecular Access (MACCS) keys that 90 % of marketed drugs have a Tanimoto similarity of more than 0.5 to the (structurally) ‘nearest’ human metabolite. This suggests a ‘rule of 0.5’ mnemonic for assessing the metabolite-like properties that characterise successful, marketed drugs. Multiobjective clustering leads to a similar conclusion, while artificial (synthetic) structures are seen to be less human-metabolite-like. This ‘rule of 0.5’ may have considerable predictive value in chemical biology and drug discovery, and may represent a powerful filter for decision making processes.

Whilst this represents an interesting observation I was rather concerned about the choice of a Tanimoto coefficient of 0.5, and decided to repeat the analysis.

The recon-2 dataset was downloaded as a Matlab file, this was exported as a plain text file and Rajarshi Guha converted them to SMILES strings and removed duplicates (and did a comparison with PAINS). I imported these structures into a MOE database and then used a SVL script to compare the recon2 with several other datasets. This included DrugBank that includes details of just under 7000 drug entries, a cleaned up subset of leadlike molecules from Zinc, and BindingDB a public, web-accessible database of measured binding affinities I downloaded in 2008. The datasets were first compared to each other using the MACCS fingerprints with a Tanimoto cutoff of 0.5.


As the table above shows using a Tanimoto coefficient of 0.5 indeed 90% of the molecules in DrugBank are similar to a molecule in recon2, however the same is true for Zinc and BindingDB, indeed at a Tanimoto coefficient of 0.5 all the datasets are pretty similar.

If we increase the Tanimoto coefficient to 0.85 we start to see some resolution, recon2 looks to have more overlap with DrugBank than with either Zinc or BindingDB. However this may simply be a reflection of the fact that DrugBank contains a significant proportion of natural product derived compounds.


The key question of course is “Does this help us to identify compounds that are likely to fail in development?”. It would be really useful to compare with successful drugs and those that fail in development however I’m not aware of any dataset of of failed drug candidates (if anyone knows of one please let me know). However to in an effort to perhaps get some insight I’ve compared the recon2 set with a dataset of drugs that have been withdrawn (for a variety of reasons). As might be expected using a Tanimoto coefficient of 0.5 offers little discrimination. Increasing to 0.85 it looks like there might be a signal there, but the dataset is too small for firm conclusions.


In summary, this limited exploration suggests there may be something worth following up, but that a Tanimoto of 0.5 simply offers little discrimination.

Bioisosteres pages updated

I’ve updated the pages on bioisosteres to include more examples.

Page on HERG updated

I’ve updated the page on HERG activity, to include a little more information on pharmacophore models.

Fragment sized drugs

As someone who regularly reads Derek Lowe’s “In the Pipeline” blog I was taken with the post on The Smallest Drugs in which he highlighted the structures using the arbitrary cutoffs

the molecular weight cutoff was set, arbitrarily, at aspirin's 180. I excluded the inhaled anaesthetics, only allowing things that are oils or solids in their form of use. As a small-molecule organic chemist, I only allowed organic compounds - lithium and so on are for another category.

An interesting selection but I thought it might be interesting to profile the calculated properties, I used the DrugBank Database too ensure I got a more comprehensive dataset and then calculated properties as I have done for the Fragment collections. The results are shown below. Probably the most notable feature is the number that contain ionisable groups, over 60% of the molecules would be predicted to be ionised at physiological pH (note however it does include a couple of natural amino acids). Around 50% contain an aromatic ring (of which 2/3 are heterocycles). There are a couple of structures with more 3D shape (Memantine) but in general they would be classified as disc or rod-like. In general the results don’t look too dissimilar to the Published Fragment Hits.


Published Fragments

I’ve updated the page on published fragments, the dataset now includes over 800 published fragments hits abstracted from over 200 publications directed at nearly 130 different molecular targets using 22 different detection technologies and might be expected to give some insight into the type of compounds that appear as hits. With the caveat that the dataset only includes information that has been published.


Seven pharma companies provide access to stalled development compounds

UK researchers will be granted access to a ‘virtual library’ of deprioritised pharmaceutical compounds through a new partnership between the Medical Research Council (MRC) and seven global drug companies, announced today by Business Secretary Vince Cable.

AstraZeneca, GlaxoSmithKline, Janssen Research & Development LLC*, Lilly, Pfizer, Takeda and UCB will each offer up a number of their deprioritised molecules for use in new studies to improve our understanding of a range of diseases. A full list of available compounds will be published later this year, when UK scientists will be able to apply for MRC funding to use them in academic research projects.

This has the potential to a really exciting resource for scientists to explore the pathways involved in a variety of different diseases, and since the compounds have apparently undergone some development it may provide a boon to those involved in repurposing drugs. Much will of course depend on the compounds offered but perhaps other companies will follow suit.

Drug Discovery Resources Updates

I’ve added two new pages to the ADME section, there are now separate pages for CYP2D6 inhibitors and CY3A4 inhibitors.

22 July 2014 Updated to include CYP2C9 and CYP2C19 inhibitors.


18th SCI/RSC Medicinal Chemistry Symposium

18th SCI/RSC Medicinal Chemistry Symposium Sunday 13 - Wednesday 16 September 2015 Churchill College, Cambridge , UK

Europe’s premier biennial Medicinal Chemistry event, focusing on first disclosures and new strategies in medicinal chemistry. Reflecting current trends in medicinal chemistry and pharmaceutical research, the theme of the conference will be ‘Drugging the Undruggable’.

A number of conference places will be reserved for poster presenters and contributions are invited from the whole field of medicinal chemistry. Those presenting a poster may also elect to advertise their poster via oral presentation of a single slide ‘flash’ poster. In addition to traditional plenary talks the organising committee wishes to solicit short talks (20 minutes) describing highly impactful but possibly less complete episodes of medicinal chemistry.

Further Information SCI Conference Dept, 14/15 Belgrave Square, London, SW1X 8PS T: + 44 (0)20 7598 1561 E: W:

Longitude Prize 2014

In 1714 the British government threw down the gauntlet to solve the greatest scientific challenge of the century – how to pinpoint a ship’s location at sea by knowing its longitude. Three hundred years later the Longitude Prize 2014 is a challenge with a £10 million prize fund to help solve one of the greatest issues of our time. It is being run and developed by Nesta, with the Technology Strategy Board as launch funding partner.

There are six potential areas highlighted all very worthy causes, however there can only be one prize winner and this is your chance to vote for your preferred project.

The Challenges

WATER How can we ensure everyone can have access to safe and clean water? Water is becoming an increasingly scarce resource. 44 per cent of the world’s population and 28 per cent of the world’s agriculture are in regions of the world where water is scarce. The challenge is to alleviate the growing pressure on the planet’s fresh water by creating a cheap, environmentally sustainable desalination technology.

ANTIBIOTICS How can we prevent the rise of resistance to antibiotics? The development of antibiotics has added an average of 20 years to our life. Yet the rise of antimicrobial resistance is threatening to make them ineffective. This poses a significant future risk as common infections become untreatable. The challenge is to create a cost-effective, accurate, rapid, and easy-to-use test for bacterial infections that will allow health professionals worldwide to administer the right antibiotics at the right time.

DEMENTIA How can we help people with dementia live independently for longer? It is estimated that 135 million people worldwide will have dementia by 2050, which will mean a greater personal and financial cost to society. With no existing cure, there is a need to find ways to support a person’s dignity, physical and emotional wellbeing. The challenge is to develop intelligent, affordable integrated technologies that revolutionise care for people with dementia, enabling them to live independent lives.

FLIGHT How can we fly without damaging the environment? If aircraft carbon emissions continue to rise they could contribute up to 15 per cent of global warming from human activities within 50 years. This needs to be addressed in order to slow down climate change and its detrimental effects on the planet. The challenge is to design and build an aeroplane that is as close to zero-carbon as possible and capable of flying from London to Edinburgh, at comparable speed to today’s aircraft.

FOOD How can we ensure everyone has nutritious, sustainable food? One in eight people worldwide do not get enough food to live a healthy and fulfilled life. With a growing population and limited resources, providing everybody with nutritious, sustainable food is one of the biggest global problems ever faced. The challenge is to invent the next big food innovation, helping to ensure a future where everyone has enough nutritious, affordable and environmentally sustainable food.

PARALYSIS How can we restore movement to those with paralysis? In the UK, a person is paralysed every eight hours. Paralysis can emerge from a number of different injuries, conditions and disorders and the effects can be devastating. Every day can be demanding when mobility, bowel control, sexual function and respiration are lost or impaired. The challenge is to invent a solution that gives paralysed people close to the same freedom of movement that most of us enjoy. Find out more & vote