Autumn 2012 Newsletter



UK-QSAR Autumn 2012

The UK-QSAR and ChemoInformatics Group

Welcome to the new UK-QSAR Newsletter!

We’ve decided  to launch a new bi-annual newsletter to help us keep in touch with our members!  Please let us know what you think of the newsletter, and send us any suggestions to improve it for future editions.  We need members to contribute articles, so please send any suggestions/feedback/ideas to us at newsletter@ukqsar.org.   This is your newsletter – please help us to make it how you’d like it!


Autumn Meeting 2012

The autumn meeting which is sponsored by Takeda Cambridge will be on Thursday 8th November 2012 at Downing College, Cambridge. The Provisional Agenda is now at http://www.ukqsar.org/2011/07/28/autumn-2012/.  If you have not already registered, please sign up soon.  Spaces are limited and are going fast!  If you have already registered and can no longer make it, please let us know so we can offer your place to someone else.



Introducing your new Chariman & Secretary of the UK QSAR & Chemoinformatics Group…..

2012……The year of the London Olympics, the Diamond Jubilee and …..drum roll…..the year the Group needs to appoint a new Chair & Secretary!  For the last few years, Brad Sherborne  and Andrew Leach have ably and enthusiastically embraced these roles, and we are all extremely grateful to them for their hard work, effort and commitment.  But the rolling stone of time rumbles onwards, and the rules say we need new posteriors to fill these seats.  The Committee elected Andrew Leach as Chair and John Delaney as Secretary a few weeks ago.  Both are of course very familiar to many members, with Andrew having previously served as Secretary and John having been on the Committee for so me time, but how much do we really know about these new Servants of the Society?  We thought we’d conduct some searching interviews to get to know these guys a little better…….

Naturally, we congratulate both Andrew & John on their new roles, we thank them for volunteering for these positions and wish them every success.

The New Chair: Andrew Leach

Most recent occupation:  Computational Chemist at AstraZeneca, Alderley Park


  • What inspired you to work in computational chemistry?
    I would describe my path to being a computational chemist as more of a random stagger than an inspired mission!
  • Can you briefly describe your career history?
    I went off to Cambridge when I was 18 intending to be chemical engineer but for the first two years of that course you either study natural sciences or engineering.  I chose the former and then never got round to changing so ended up in chemistry.  I did a project with Jonathan Goodman in my final year and then stayed on to do a PhD with Steve Ley in synthetic chemistry.  After that I went back to computation and did a post doc with Ken Houk at UCLA.  On returning to the UK I joined AZ as a computational chemist and have been there ever since.
  • How do you think computational chemistry/chemoinformatics most benefits pharmaceutical research?
    By doing its best to make sure that no experimental effort is wasted on things that we could have predicted would not be worth the effort.
  • What do you think the key areas will be for the future of computational chemistry/chemoinformatics?
    I have always felt that the key gap in our toolbox is modelling how molecules interact with their environment whether that is a protein, solvent, membranes, crystal lattice or anything else.
  • How can we inspire new students to take up the discipline?
    I fear that I am not sure that it is currently fair on students to try and do this (see below).
  • How do you see career prospects for modellers in the coming years?
    Certainly within the drug discovery context I fear the prospects are pretty bad and geographically extremely localized.
  • What role do you envisage for the UK QSAR & Chemoinformatics Group in the next few years?
    Although the old BT motto is a rather trivial way of summarising it, I think its effective: Its good to talk. I think we have always been a great forum for connecting the various computational chemists employed in lots of sectors and I hope that we continue to do that as computational chemistry is deployed in the new organisations that I hope will crop up.  We need to make sure that we keep our eyes open as the industrial science base of the UK evolves. 
  • What is your favourite hobby when you’re not working?
    I’m a brass band player.  I currently play tenor horn with Sale Brass Band.
  • How cheesed off do you get at being confused with “The Other Andrew Leach” and how often does it happen??!
    Far from being cheesed off, Andrew has been a great person to be confused with although sadly the confusion happens less and less these days!
  • How do you eat a Cadbury’s Crème Egg?
  • Marmite or peanut butter?
    Neither.  Bleurgh.


The New Secretary: John Delaney

Current occupation:  Syngenta, Jealott’s Hill

  • What inspired you to work in computational chemistry?
    Bill Mackie (Leeds Uni) telling me how lysozyme works at my undergraduate interview (1982).
  • Can you briefly describe your career history?
    Biophysics at Leeds, straight to a job at ICI Plant Protection Division at Jealott’s Hill after graduating (1986). An illusion of career progression has been maintained by the company changing its name every 7-8 years.
  • How do you think computational chemistry/chemoinformatics most benefits crop protection research?
    We often find that relatively “simple” stuff like physical property prediction and statistical analysis of in-vivo data can have a huge impact on crop protection research. Just wrestling the data into a tractable form for QSAR etc. is very valuable.
  • What do you think the key areas will be for the future of computational chemistry/chemoinformatics?
    Better physics and better stats (to cover the shortfalls in the physics!). I think there’s a huge opportunity in better understanding time dependences in compound optimisation – is the order compounds are made important?
  • How can we inspire new students to take up the discipline?
    Believe that the science can make a difference and communicate that belief … by giving a talk at a UK QSAR meeting.
  • How do you see career prospects for modellers in the coming years?
    Tricky – big pharma is changing and it’s not clear what that’s going to do to the employment landscape. I’d come back to the point above – if the science is truly useful, someone will pay you to do it.
  • There are a few John Delaneys around (though none of them are computational chemists it would seem!).  Do you ever get confused with any of them?
    Well, between my other roles as head of the Irish FA,  mayor of Jacksonville, prediction market entrepreneur, hurler and oceanographer I don’t have time to worry about it.
  • What is your favourite hobby when you’re not working?
    Playing guitar (badly) and Gran Turismo 4 (brilliantly).
  • How do you eat a Cadbury’s Crème Egg?
    Two big bites – gone!
  • Marmite or peanut butter?
    Peanut butter.

News – Committee Changes

In addition to the above changes, there have been a few more modifications to the make-up of the Organising Committee in recent months.

After many years serving on the Committee, Peter Gedeck and Mark Cronin have decided to stand down.  We thank them both for their considerable contributions, and in turn welcome Peter Hunt (Novartis) to the Committee.


Computational Methods in Translational Research

Susan Boyd

We know all too well the changes which have been happening in the pharmaceutical industry in the last few years.  Since Derek Lowe’s post on the topic last year (http://pipeline.corante.com/archives/2011/04/14/total_pharma_job_cuts.php), the number of casualties has continued to swell with job losses at AstraZeneca, the announced closure of Cellzome in Cambridge (UK), cuts at Merck Serono across Switzerland and likely cuts at Roche and Novartis in the USA.  So what does the future hold for the pharma industry?  Chris Swain has published a very interesting article on the topic recently (see http://www.samedanltd.com/magazine/11/issue/175/article/327).  There seems to be general consensus, however, that one growth area in computational chemistry in recent years has been in translational research.  I set out to explore exactly how in silico methods are helping this sector by speaking with some of the key players involved.

Due in no small part to the increasing drive towards open innovation in pharmaceutical R&D, many academic groups are now actively involved in drug discovery research. Computational chemistry and computational biology can be valuable tools in helping to convert discoveries and ideas into new therapies with real application to disease and illness. At MRCT, for example, Dr Andy Merritt’s computational chemistry group focus much of their effort on support of internal medicinal chemistry projects through use of structure-based design methods and SAR-rationalisation, but they also contribute significantly to design of the MRCT proprietary screening collection, the design of 3D fragments, and to supporting early stage academic structural biology projects.

Naturally, much early discovery work is centred around discovery and validation of potentially interesting new targets, which are often identified by cell-based screening approaches. Computational chemistry & biology approaches can be used to help identify a range of possible therapeutic applications of such targets, and can assess the likely druggability/ligandability of the targets. An example of this is the concept of senescence scoring from the CRUK-funded Beatson Laboratories (http://www.biomedcentral.com/1471-2164/11/532), whereby the concept of “senescence profiling” was explored to examine the levels of senescence signals in various tumours. The senescence scores were based on expression profiles of senescence biomarkers from phenotypic data. The correlation of senescence scores with growth inhibition in response to around 1500 compounds which had been screened for toxicity was explored using a binary decision tree algorithm which predicted likely activities of the 1500 compounds. From the study it appears that senescence scores may predict cellular therapeutic sensitivities, as differing subsets of the dataset (as defined by differing senescence signatures) appear to be enriched in different pharmacophoric elements predictive of gene family propensity.

Similar or related approaches can also be used to predict off-target effects of compounds, to explore drug repositioning opportunities or simply to assess target tractability for small molecule approaches.  Construct design is a key component of protein crystallography programmes, and computational methods can be of great benefit to design by identifying similar structures/sequences and using these to predict likely insert/deletion regions and to identify domain boundaries.

Of course, more traditional computational methods can also be applied to support medicinal chemistry programmes, including hit finding, scaffold hopping and lead optimisation projects.

Translational research is often funded by grant awarding bodies/charities, requiring researchers to devote considerable energy and time to develop grant applications.

At Cancer Research Technology computational chemistry is used primarily where protein structural information is available, but increasingly they have seen benefit in the application of computational approaches to assess new projects for target tractability.  Dr Tony Raynham, Head of Chemistry says “At CRT we’ve found that comp chem has accelerated research in several of our programmes, and we are increasingly using comp chem to help validate targets early in the discovery process.  We see in silico approaches as an integral part of our discovery efforts.”

So there you have it.  Comp chem is already proving pretty handy to have around in translational research, but if we can expand our armoury to devise even better ways to tackle the target tractability/druggability conundrum, there could be great opportunities for us in the future


Computer-Aided Drug Discovery (CADD) Scientist – Novartis, Basel

(added Oct 1st  2012)

We are looking for an outstanding CADD scientist with experience in the application of cheminformatics, modelling and computational chemistry techniques to target assessment, hit finding and lead optimization; the key objective of the role is to impact discovery projects and to strengthen collaborations with biologists and chemists working to discover new medicines.

Responsibilities include:

  • Taking accountability to answer key scientific issues in discovery projects
  • Communicating results to cross-functional and global teams
  • Doing innovative science to impact discovery efforts
  • Identifying, championing and leading academic collaborations


The successful candidate should be an established CADD Scientist with proven track record of contributions to discovery projects, exemplified by publications and patents; candidates who have contributed significantly to the successful delivery of a clinical candidate will be preferred.

The ideal candidate will be competent in written and oral communication skills, well organised with good time management. Further, he / she will be professional, cooperative, self motivated and able to take the initiative. We look for a strong team player with good interpersonal skills who has an understanding of team dynamics and of how to make high impact in a drug discovery environment

To apply, please upload your CV, covering letter, which should include a reference to this advertisement (CADD Investigator at Basel, 104185BR), and any other documentation you would like us to consider through the link in this website: http://nibr.com/careers/.


Vacancy for a Database Curator (Chemoinformatics) – University of Edinburgh

(added Aug 28  2012)

You would join  the team developing the IUPHAR Database (http://www.iuphar-db.org) and the Guide to PHARMACOLOGY (http://guidetopharmacology.org).

The post requires a postgraduate qualification in chemoinformatics or equivalent experience; you would play the lead role in the curation of the chemistry content of the databases. Further details are available on the University of Edinburgh website

(http://www.jobs.ed.ac.uk) under vacancy reference 3016163.

Tony Harmar FRSE                                    tony.harmar@ed.ac.uk

Professor of Pharmacology

University/BHF Centre for Cardiovascular Science Queen’s Medical Research Institute University of Edinburgh

47 Little France Crescent

Edinburgh, EH16 4TJ, Scotland

Tel +44 131 242 6693 FAX +44 131 242 6782 http://www.guidetopharmacology.org


The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336.


Porter’s Papers – A review of recent literature from Rod Porter

(Full text of Rod’s bi-monthly newsletters, which include med chem literature reviews in addition to the more general/comp chem papers included here, can be found on his website at http://rodporterconsultancy.com/newsletter/)

Molecular properties and in vitro and in vivo toxicology and disposition

An important contribution from the group at Lilly 1 outlining their analysis of physicochemical and ADMET properties with PK and toxicology data on some 3,773 compounds from 173 different chemical classes. Firstly the authors provide a critique of the numerous previous studies which have analysed physicochemical properties of compounds in relation to toxicology or surrogates of toxicology readouts pointing out the lack of consideration in many of covariants for example the relationship between solubility and molecular weight should also perhaps consider the impact of ionisation or lipophilicity as well.

The study highlighted the importance of rat in vitro hepatocyte toxicity combined with volume of distribution for in vivo toxicology (LOAEL based on histology or death) outcomes and microsomal clearance with cLogP for predicting unbound clearance. Higher clearance looked like bad news for toxicology as well all of which tends to make intuitive sense but now with a sense of quantitation. Indicators of oral bioavailability were weak – decreasing PSA or increasing solubility gave modesteffects on improving bioavailability with permeability also only having a minor impact

Further work was done to look at the effects of single point changes in structure, however within the constraints of the data set there were not too many surprises. Having said that I did find it a little surprising that replacing a CF3 with F gave an increase in LOAEL and replacing F with H gave a further increase although as the authors admit the sample sets were small. I also found the observation that Vdss is reduced going from a nitrile to a methyl group but I suspect here that context is all as this is looking at the point substitutions in isolation and ignoring long range electronic effects. I think this is a valuable paper particularly with its focus on toxicology outcomes but taking a slightly different approach to the Pfizer groups analysis 2 of their tox data.

1.      J.J. Sutherland et al, J. med. Chem. 2012, 55, 6455

2.      J. D. Hughes et al, Bioorg. Med. Chem. Lett., 2008, 18, 4872

Managing PPI’s

Protein-protein interactions are being seen increasingly as attractive albeit tough targets. PPI’s vary from clefts much like a ligand-protein binding site through to large fairly flat systems perhaps with a few binding hotspots. Generally success has been achieved in targeting the former and not the latter. In a recent review 1 the authors summarise the approaches that might be taken to address the latter targets in particular. Strategies discussed include allosterism and intervening in post translational modifications. Nature can also provide inspiration, cited for example, is the role of vinblastin in microtubule destabilisation. This is a short review but for those of you interested in PPI’s a useful summary. I guess in a similar vein a paper 2 from a group at Genentech discusses RAS inhibition via direct RAS binding by compounds – a number of agents are known that show activity although affinities are generally low e, g (1), (2). The authors highlight the challenge is now to increase the activity of these compounds and selectivity particularly with respect to other GTPases.

A recent paper 3 discusses the use of virtual screening to identify inhibitors of the JNK-JIP1 interaction. This has been an active area of research with a number of inhibitors identified. The authors used one of these inhibitors BI-78D3 to identify in silico where it may bind to JNK and a putative bound conformation using the crystallographic data for the JNK-JIP1 interaction. A virtual screen of the NCI Diversity Set generated a number of hits which gave IC50’s for displacement of JIP from JNK of between 0.7 and 22uM. Not a perfect story perhaps but a demonstration that “conventional” techniques have value for PPI’s when appropriately used.

1.      A. Thompson, et al, ACS Chem. Biol., Article ASAP, DOI: 10.1021/cb300255p Publication Date (Web): July 23, 2012

2.      W. Wang et al, Bioorg. Med. Chem. Lett., 2012, 22, 5766

3.      T. S. Kaoud et al, Med. Chem. Lett., Article ASAP DOI: 10.1021/ml300129b Publication Date (Web): August 13, 2012


So far so not so good – 2012

Just noted 1 that for the first two quarters of 2012 there have been 12 new FDA drug approvals (NCE and biologics) this compares with 30 at the same stage last year. Two of the approvals this year were the two anti-obesity drugs – not exactly new compounds bearing in mind how long it took them to get approval. So the article I rerviewed last time talking about 2015 as perhaps crunch tiime when the reduced PhI pipeline catches up with launches perhaps looked a little optimistic.

1.      L. DeFrancesco Nature Biotechnology 2012, 30, 817


Learning lessons

A short article from Richard Elliott at the Gates Foundation suggesting some lessons that pharma can learn from those working on neglected diseases – disease areas working in a lean business environment. Briefly they are

  • Go for compounds not targets that is advocating phenotypic screening – broadly hard to argue with except there are major areas of unmet medical need such as CNS where phenotypic screening can be tough.
  • Consider compound libraries as pre-competitive, the IP tends to be found in what was done after the hit was identified.
  • Be open minded – citing Lipinski as an example of guidelines that became unbreakable rules.
  • Have a long term strategy and stick with it – now that would be nice!

I guess we could all add few more items to this list.

1.      R. L. Elliott ACS Med. Chem. Lett., Article ASAP DOI: 10.1021/ml3002105


Why we are here

As a research worker it can be easy to get a little detached from why you spending ludicrous hours working on a particular problem – or lets face it a small part of a larger problem when it comes to drug discovery. I thought this article 1 was a timely reminder of the importance of reminding ourselves why we got into our chosen career. Very simply it is the story of a graduate student who organized a meeting of people affecting by Alzheimers disease, patients, carers, and research workers. Bottom line of this was that not only were the researchers re-enthused for their work but the patient/care group benefited enormously as well. As the author pointed out patient communities spend a lot of time raising money for research and the researchers spend most hours of the day trying to discover treatments but direct contact is rare. Its only a page long but worth a read.

1.      T. Nuriel Nature 2012, 487, 7