Summer 2018 Newsletter

Summer 2018 Newsletter

Welcome to the Summer 2018 Newsletter from CompChem Solutions Limited.

AI seems to be the Big New Thing to hit drug discovery, but what is it likely to deliver?  We take a look at some of its potential strengths, and also at some of the criticisms levied at the new technology .

Closer to home, CompChem Solutions has partnered with Lhasa Ltd, and is able to offer Meteor consultancy services for metabolite prediction.

As ever, do check out our listings of some upcoming events and jobs which may be of interest to our readers as well as our In Brief section for a brief round-up of news items from CompChem Solutions.


In Brief

  • We are delighted to have become a Meteor Consultancy, using Lhasa’s Meteor Nexus tools for metabolite prediction
  • The Cresset User Group Meeting is fast approaching (211-22 June) – see you there if you can make it!
  • If you need patent or chemical information searching services, do contact us!
  • The date and venue for the Autumn UK-QSAR Meeting have now been set.  It will be at the beautiful Lady Margaret Hall in Oxford, on 26th September.
  • Remember that CompChem Solutions is a CDD Advocate. Do check out their blog for news on how their flexible, intuitive tools are benefiting their customers, and contact us if you’d like more information.



CompChem Solutions partners with Lhasa as Meteor Consultant

Susan M Boyd, CompChem Solutions Ltd

CompChem Solutions Ltd is delighted to have become an Meteor Consultant with Lhasa Ltd.   Meteor Nexus is an expert, knowledge-based system for prediction of both Phase I & Phase II metabolites, based on experimental data.  The approach is applicable not only to pharmaceuticals, but also to the wider chemical industry including cosmetics, crop protection and neutraceuticals.  CompChem Solutions evaluated Meteor’s performance against a drug with characterised experimental metabolites and the results were impressive.  The vast majority of the known metabolites were correctly predicted, and additional feasible metabolites were proposed.  If you’d like to use Meteor against some of your own compounds then  contact us for further information.


AI: Panacea or Flash in the Pan?

Susan M Boyd, CompChem Solutions Ltd

AI seems to be the New Big Thing in our industry. with money pouring into any business who purport to have expertise in the area.  Every major pharmaceutical company has been investing in in-house AI or partnering with others to develop their own systems, and AI-focused biotechs are booming.  Even the seriously big boys – IBM Watson, Google & Microsoft are getting in on the act.  So is this really the start of some huge new leap across our computational landscape, with our good old 1990s Artificial Neural Networks, Support Vector Machines and Random Forest algorithms all grown-up now, or is it all, er, just a wee bit over-egged?


Deep Neural Networks for Drug Discovery from Insilico Medicine Inc


Some drug discovery applications lend themselves very nicely to deep learning approaches – synthetic route design, connecting seemingly disparate biochemistry to  predict alternative uses for known drugs, and de novo ligand design, and already there are reports of AI being used with very good results in these applications.  Other computational tasks such as bioactivity prediction may be less obvious beneficiaries of the new technologies, and indeed, it is unclear at present whether these AI technologies will offer any marked improvement over conventional docking scoring functions.

There is little doubt that Deep Learning (DL) has had great success in many areas, such as self-driving cars, computer games and speech recognition, but in some quarters the current frenzy of excitement around AI in drug discovery is coming in for some criticism because incomplete or unsatisfactory data is being reported which could enhance the perceived success of the AI approach.  In such cases, seeking an independent, expert opinion of a potential AI partner’s technology could be useful before signing on that dotted line.

This really is an exciting area, and I predict is has some way to run yet.  In time, I predict that some applications of AI may indeed revolutionise our science, but that in others it may not be, well, all it’s cracked up to be. I could be wrong, and in 10 years time it will be a machine-learning algorithm that’s sitting writing this newsletter!




The following meetings may be of interest to our readers:

RSC/SCI Kinase 2018, 14-15th May, Cambridge, UK.

Cambridge Chemoinformatics Network Meeting, 16th May, Cambridge, UK.

CCG European User Group Meeting, 15-18th May, Basel, Switzerland.

ICCS Chemical Structures Conference, 27th-31st May, Noordwijkerhout, The Netherlands.

Cresset User Group Meeting 2018,  June 21-22nd, Cambridge, UK.

MGMS Discrete Models and Formal Verification in Biology, 29-31 Aug, Cambridge, UK.

EuroQSAR 2018, 16-20 September, Greece

UKQSAR Autumn Meeting, 26 September, Oxford, UK.



Some current jobs being advertised…….

Machine learning & chemoinformatics specialists, AstraZeneca, various locations.

Senior Computational Chemist (Fragment-based lead generation), AstraZeneca. Cambridge, UK

Post Doc Fellow – Bayesian Machine Learning, AstraZeneca, Cambridge, UK

Post-doc Fellow – De novo molecular design using deep learning, AstraZeneca, Gothenburg, Sweden

Post Doc Fellow – Predictive chemistry tools for route design, AstraZeneca, Macclesfield, UK

Various positions,, London, Cambridge, New York.

Application Scientist, CCG Inc, Cambridge, UK or Cologne, Germany.

Head of Software Development, CCDC, Cambridge, UK.

Head of Science, CCDC, Cambridge, UK.

Computational Chemist, Cresset, Cambridge, UK.

Free CDD Webinar on Antibiotic Resistance

On March 22nd 2018 CDD are hosting what looks to be an excellent webinar discussion on overcoming  the challenges of gram-negative antibiotic resistance.  Do register if this is your thing!

Spring 2017 Newsletter

Spring 2017 Newsletter


Welcome to the Spring 2017 Newsletter from CompChem Solutions Limited.

We’re delighted to announce our new Advocate partnership with Collaborative Drug Discovery (CDD).  CDD offers a modern approach to management of discovery informatics.  More information is below.

Every so often huge strides are made in a particular therapeutic area.  One recent example of this, which has employed quite extensive use of computational structure-based design approaches, is in the area of B-cell haematological oncology.  Two newly approved drugs for CLL/SLL, ibrutinib & venetoclax, were both developed with the aid of structural design.  We feature an article on these game-changing therapies, and invite scientists working in this field to propose new targets for future therapies.  CompChem Solutions may be able to provide limited fee-free support for development of grant proposals in the haematological oncology area.

We’ve been beta-testing Cresset’s new Flare application, which now enables inclusion of proteins to Cresset’s unique field-based approach.  Their User Group Meeting is only a few weeks ago so do attend if you’d like to learn more about Flare and their other recent innovations.

The next UK-QSAR meeting is approaching fast – we hope to see you there!  Do register if you’re planning to attend as time is running out.  And it’s nearly time for the CCG UGM too if you’re up for a trip to Copenhagen next month.

Do refer to our listings of all our selected upcoming events and jobs as well as our In Brief section for a brief round-up of news items from CompChem Solutions.

 In Brief

  • Susan Boyd has recently co-authored a  publication from Cancer Research Technology on “The development of potent inhibitors of the lysophospholipase autotaxin”
  • We’ve been delighted to to take a first look at Cresset’s Flare software for modelling protein systems using their field-based approach.  Further beta testing is now underway.
  • If you need patent or chemical information searching services, do contact us!
  • Do register for the UK-QSAR Meeting if you plan to attend!  And please let us know if you’ve already registered but can no longer attend.

CompChem Solutions partners with Collaborative Drug Discovery

Susan M Boyd, CompChem Solutions Ltd

CompChem Solutions Ltd is delighted to have become an Advocate partner for Collaborative Drug Discovery (CDD).   CDD offers a modern approach to research informatics, with their Vault application hosting a secure biological & chemical database platform which is simple to use and ideally positioned for use by small and large drug discovery teams alike. Their secure web-interfaced system includes tools for molecular visualisation, an ELN, a compound inventory as well as tools for logging compound activity and registering compounds, and is designed to support ready sharing of data across sites and between teams.  Contact us for further information.

Structure-based design has helped change the landscape of B-cell targeted oncology

Susan M Boyd, CompChem Solutions Ltd

Until quite recently, the only therapies available to patients with chronic  lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) were “traditional” chemotherapy approaches.  These typically involve the use of a combination of alkylating agents, antibodies and sometimes T-cell/immunosupressants.  However, the side effects of these treatments can be significant, their effects last for at best the medium term, and they may even precipitate unfavourable clonal changes in cells to predispose the patient to complications or even secondary cancers further down the line.

In 2013, the whole landscape of treatment for these B-cell cancers was revolutionised, with the FDA approval of ibrutinib.  Ibrutininb, or Imbruvica, is an irreversible inhibitor of Bruton’s Tyrosine Kinase  (BTK), and instrumental in its development was the use of computationally-driven structure-based approaches to guide compound design (Pan et al, ChemMedChem, 2, 58-61, 2007).  The drug sits in the ATP binding site of BTK, covalently bonding to C481.  Initially a homology model of activated BTK was derived based on the unphosphorylated BTK structure 1K2P and the active structure of LCK kinase 1QPE.

From this the non-catalytic cysteine was identified and analogues synthesised and subsequently optimised, resulting in the final drug compound.  The compound was FDA-approved for mantle cell lymphoma in 2013,then for specific forms of CLL/SLL in 2014.  In the UK NICE finally approved its use for specific CLL/SLL patients at the end of 2016. Clinical trials have shown remarkable efficacy.  The RESONATE trial demonstrated an over 90% response rate to ibrutinib compared with 25% rate in the standard treatment.

Following close on the heels of ibrutinib, apoptotic regulator BCL-2 inhibitor venetoclax (aka ABT-199) was designed based on the known BCL-Xl/BCL-2 inhibitor navitoclax.  Navitoclax itself shows dose-limiting thrombocytopenia toxicity, and it was considered that this was likely due to its lack of selectivity towards BCL-Xl.  Reverse engineering of navitoclax together with peptidomimetic design studies on other hot spot regions of the BCL-2 site were used to develop the BCL-2 selective compound venetoclax (Souers et al, Nature Medicine,19(2), 202-208, 2013). 

It was approved for use in specific CLL/SLL patients by both the FDA & the EMA in 2016.  It is still under consideration by NICE in the UK but has been approved for inclusion in the Early Access to Medicines Scheme (EAMS) and has shown an over 80% overall response rate in early clinical trials, whilst showing a highly favourable safety profile.

These drugs are true game changers in this field of oncology, and other so-called “pathway” therapeutics have also emerged, such as idelalisib.  However, the future of treatment of B-cell cancers may well lie in the use of combination therapies, involving single or multiple small molecule agents combined with antibody use.  Many clinical trials are ongoing and this is a truly exciting area of research.  There has been some concern over reports that inhibitors of the PI3Kdelta pathway,  including ibrutinib itself may themselves induce increased expression of activation-induced cytosine deaminase (AID) over the long term, which may lead to genomic instability and to development of lymphoma.  Further studies are certainly needed to establish the level of resistance to these newer drugs, and to explore their long-term usage safety.  There is still a very great need for alternative and/or improved therapies.

If you have a potential drug target which might be of use in future therapies B-cell malignancies, do get in touch.  We may be able to provide limited support free of charge in terms of structural assessment of druggability of targets and to provide background information in support of grant applications.




The following meetings may be of interest to our readers:

CCG UGM & Conference (Europe), 16-19 May 2017, Copenhagen

Symposium on Streamlining Drug Discovery (Optibrium, BioSolveIT, Lhasa & Takeda), 18 May 2017, Cambridge

Cambridge Chemoinformatics Forum, 24 May, Cambridge

Cresset UGM, 29-30 June 2017, Cambridge

UK QSAR & Chemoinformatics Group Autumn 2017 Meeting, 29 September 2017,  MIB, Manchester

SCI Epigenetics 2017, 7 September 2017, Windlesham, Surrey

19th RSC/SCI Cambridge MedChem Symposium, 10-13 September 2017, Churchill College, Cambridge


Some current jobs being advertised…….

Team Leader (CADD), Charles River Laboratories, Saffron Walden, Essex

Application Scientist, Chemical Computing Group Inc, Cambridge (UK) or Cologne (Germany)

Senior Scientific Consultant, Cresset Group, Litlington, Cambridge, UK

Product Manager (API), RSC, Cambridge, UK

Chem- and Bioinformatics Scientists, Software Engineers, Machine Learning Researchers,, London, UK

CompChem Solutions Ltd teams up with Collaborative Drug Discovery

CompChem Solutions Ltd is delighted to have become an Advocate partner for Collaborative Drug Discovery (CDD).   CDD offer a modern approach to research informatics, with their Vault application hosting a secure biological & chemical database platform which is simple to use and ideally positioned for use by small and large drug discovery teams alike.  Contact us for further information.

Summer 2016 Newsletter

Summer 2016 Newsletter

Welcome to the Summer 2016 Newsletter from CompChem Solutions Limited.

Well, they say a week is a long time in politics but, boy, this last one must surely count as one of the most dramatic episodes in living memory for most of us.  What will happen next?  When will some new normality condense from the fall-out?  We may not know the answer to these, and may other key questions, for some time yet, but we kick off this time with a synopsis of how the vote has thus far affected our area of science, and what impacts the vote could have for us going forward.  Prior to the  vote, the Cresset European User Group Meeting was held near Cambridge, and here we have penned a personal perspective on the key highlights of what was an excellent meeting.   Further to the strides which have been widely reported recently in the Alzheimer’s field, we feature an article from Christina Elliott of the Killick group at KCL, who reports on the emerging role of inflammation in the condition, and how this may be a key area for development of therapeutics towards this devastating condition.   In other developments a new science park is planned around the theme of “big data” at Downham Market – evidence of the Cambridge effect spilling out into the surrounding region perhaps?  Do refer to our listings of some upcoming events and jobs which may be of interest to our readers as well as our In Brief section for a brief round-up of news items from CompChem Solutions.  But we end this time on a rather sad note, paying tribute to the great Mike Tute who sadly passed away at the end of June.

 In Brief

  • We’re delighted to be helping Cresset alpha and beta test their new protein modelling applications.
  • Need to outsource chemistry?  We can link you up with high quality, cost-effective offshore chemistry resource which can be project managed by UK-based medicinal chemists with extensive experience in the area.  Contact us for more information.
  • IOTA Pharmaceuticals are seeking a computational chemist for an 18-month posting based in Cambridge.  Do contact us if interested.


Brexit & Pharma

Susan M Boyd, CompChem Solutions Ltd




Perhaps surprisingly, in the wake of the recent leave vote, pharmaceutical shares appear to have risen rather than plummeted – somewhat against the general trend.  Certainly investors are looking for industries where profit reliance is beyond our immediate doorstep, and they seem to have put the pharma industry into that basket.  But will this last?  The ABPI warned immediately after the result was announced that the industry faces “immediate challenges”.  Regulation of new drugs and access to the single market are, of course, key issues, but more fundamentally the level of EU funding & investment which feeds our industry is in jeopardy.  We employ many people from EU countries, and currently UK employees can be easily seconded to overseas posts within the EU, but all of this will be more difficult in the future.  Most of the leaders of our industry supported the Remain campaign and warned of the risks of Brexit.  A very nice review of some specific aspects of the probable effects can be found here.  Going forward, we must prepare for a lengthy period of uncertainty for our industry, and hope that jobs will not be put at risk.



Cresset User Group Meeting – Top Highlights (A Personal Perspective) Cresset

Susan M Boyd, CompChem Solutions Ltd

At the end of June month I enjoyed the Cresset User Group Meeting at Granta Park, Cambridge.  The well-attended meeting was competing with the England-Wales football match which was being broadcast simultaneously, but remarkably few attendees were visibly checking portable devices during the meeting – howzat for a testament to the interesting talks presented!  There were too many great talks to go through all in depth, but here are my personal highlights from the meeting:

  • Cresset protein modelling tools unveiled:  Cresset has been recognised as a leader in the field of ligand-based modelling for some time, but they are now developing pioneering approaches to apply their field-based technology to explore protein-ligand interactions.  The initial application allows visualisation of protein-ligand interactions from a field-based perspective to aid structure-based design, plus calculation of electrostatics and looking at the “happiness” of placed waters with 3D-RISM. Their collaboration with BioMolTech will allow them to link the LeadFinder docking tool into their application and initial results look very positive.  It is hoped that their protein application will be available for release in March 2017, following on from a and b-testing by experienced Cresset users.  CompChem Solutions is delighted to be helping with this testing phase over the coming months.

                                                          Cresset protein


  • Spark case studies: Cresset described how the ensemble of databases supplied with Spark has been expanded to include new databases such as the eMolecules reagent database and the CSD fragment database.  Some inventive uses of the tool were also described, illustrating how it can be used in fragment growing, linking, macro-cyclisation and water replacement.
  • Multidrug resistance (Mire Zloh, University of Hertforshire): Multidrug resistance is obviously a major issue in drug development.  Mire described a nice approach which looks at escort molecule/efflux pump substrate complex formation as a means to attenuate efflux action.  Potential escort molecules for known substrates were identified using a combination of molecular similarity searches and ligand-ligand docking studies.  In a validation study 3 compounds known to act synergistically with antibiotics were identified and 2 molecules which can modulate efflux with these antibiotics were discovered.
  • Prediction of cyclic peptide passive permeability (Sandeep Pal, GSK):  The passive permeability of cyclic peptides is influenced by lipophilicity and intramolecular H-bonding, which has the effect of masking some polar features of the structure.  For larger molecules it is harder to derive useful 2D descriptors of polarity due to the molecular complexity. Improvement in passive permeability and absorption is often linked to increased lipophilicity.  Sandeep described a nice PLS-DA (Partial Least Squares Discriminant Analysis) classification model based on the ChromLogD descriptor (lipophilicity) and solvation energy which can nicely predict molecules as permeable or non-permeable in tests at GSK.
  • Analysing building block diversity for DNA encoded libraries (Finton Sirockin & Nikolaus Steifl, Novartis):  Finton & Nikolaus described the use of rooted 2D fingerprints and modified invariant fingerprints, combined with Cresset’s 3D field approach and attachment point vector alignment to select diverse building blocks for DNA encoded libraries.  Clustering of the Cresset field-points was used to select reagents which spanned the available molecular space.  The approach can be used to select reagents directed at particular protein targets, and to ensure that “islands” of similar compounds exist in a library to facilitate SAR exploration post-screening.


An emerging role of inflammation in Alzheimer’s disease

Dr Christina ElliottKing’s College London, Department of Old Age Psychiatry and Dementia,  Maurice Wohl Clinical Neuroscience Institute

Alzheimer’s disease (AD) is characterised by progressive cognitive impairment arising from synaptic dysfunction and eventual neuronal loss.  Most research has mainly focussed around the classic AD pathologies, the deposition of extracellular amyloid-β (Aβ) plaques, and the intracellular formation of neurofibrillary Tau tangles.  However, there has been a steady accumulation of circumstantial evidence highlighting a role of immune mechanisms in the development of AD, particularly the identification of TREM2 (triggering receptor expressed on myeloid cells) and other immune components in genome wide association studies in both genetic and sporadic forms of the disease.

While this provides a smoking gun, immune activation in AD has been often dismissed as merely an unfortunate consequence of the large scale death of neurons occurring within the AD brain.  However, a number of prominent papers published this year paint a more intimate picture, where immune mechanisms are closely involved in excessive synapse pruning, arguably the initial event in AD pathology.

One such mechanism is the complement cascade, a family of proteins traditionally involved in the clearance of opsonised microbes by phagocytosis.  In their paper, published in the journal Science, Hong et al. demonstrate that complement proteins are crucial for removal of synapses by tagging them for destruction by microglia phagocytosis.  Moreover, the authors show that exposure of neurons to Aβ can inappropriately activate this cascade leading to excessive synapse loss1.  It is also of note that complement mediated synapse loss has also been demonstrated in schizophrenia2.  Therefore, further elucidation of these mechanisms will be of broad significance and may provide therapeutic benefit to a number diseases underpinned by synaptic dysfunction.

Another strategy to attenuate immune mediated synapse loss is by the use of anti-inflammatory cytokines such as interleukin-33 (IL-33) as described by Fu et al. in PNAS.  In a mouse model of AD the authors show that administration of IL-33 can skew microglia towards an anti-inflammatory phenotype leading to preservation of cognition and a reduced amyloid plaque burden3.

It must be noted that the anti-inflammatory action of IL-33 has identified previously in Multiple Sclerosis (MS), a neurological disease where the immune component contributing to disease pathology has been formally demonstrated.  In fact a number of immune modulating drugs approved for the treatment of MS have been proposed to be of benefit in AD.  One such example is FTY720/Fingolimod, which has been shown to be protective against Aβ induced cognition loss in rodents4.

Together these works and many others demonstrate a crucial role for neuroinflammation entwined within the heart of AD pathology.  This provides a plethora of therapeutic opportunities from novel targeting of affected pathways to repurposing of licenced drugs currently in clinical use for other immune-linked disorders.

  1. S. Hong et al., Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712-716 (2016).
  2. A. Sekar et al., Schizophrenia risk from complex variation of complement component 4. Nature 530, 177-+ (2016).
  3. A.K. Y. Fu et al., IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proceedings of the National Academy of Sciences of the United States of America 113, E2705-E2713 (2016).
  4. M. Asle-Rousta, Z. Kolahdooz, S. Oryan, A. Ahmadiani, L. Dargahi, FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (A beta(42))-Induced Impairment of Spatial Learning and Memory in Rats. Journal of Molecular Neuroscience 50, 524-532 (2013).


Centre for Advanced Knowledge Engineering – coming soon to Downham Market

Susan M Boyd, CompChem Solutions Ltd

Plans are well underway for a new £350M big data campus at Downham Market after a successful open consultation meeting held recently in the Town Hall.

Big Data has become big in biotech/pharma right now, with GSK already collaborating with the EBI & the Wellcome Trust Sanger Institute on a big data project to aid target validation, and many other big players (eg AstraZeneca, Sanofi, Allergan, Roche) heavily invested in the field.  Applications of big data in pharma include custom applications for specific business problems, scientific search, competitive intelligence, medical affairs and drug repositioning.  A nice article from McKinsey  describes how big data can “revolutionize big pharmceutical R & D”.

The Centre for Advanced Knowledge Engineering (CfAKE), would be at the former RAF Downham Market in Bexwell, and is expected to create more than 4,500 permanent jobs if planning permission is approved.

The development will include improved infrastructure including faster broadband, road improvements and a university technical college.  An outline planning application for the site is being submitted this month and, if permission is granted, building is expected to begin towards the end of the year.

The project is supported by Aventa Capital, a finance group who have a successful track record in long-term value through regeneration investments in the UK that generate positive economic growth and transformational social impact.


Mike Tute

Susan M Boyd, CompChem Solutions Ltd

It is with great sadness that I learned that Mike Tute passed away at the end of June.  Mike worked at Pfizer in Sandwich for many years and I have the privilege of sharing an office with him for a short period of his “semi-retirement” during my time there.  Mike was one of the true pioneers of our field, beginning his career as a medicinal chemist before becoming a founding member of the Pfizer UK computational chemistry team.  Mike was an approachable, warm, and incredibly talented man with genuine enthusiasm for his science.  He will be missed.



The following meetings may be of interest to our readers:

7th Joint Sheffield Chemoinformatics Meeting, 4-6th July 2016, University of Sheffield

UK QSAR & Chemoinformatics Group Autumn 2016 Meeting, 19th October 2016, ICR Sutton

21st EuroQSAR Meeting, 4-8th September 2016, Verona, Italy

Sir Simon Campbell – Science, Art & Drug Discovery, SCI lecture (free but registration necessary), 27th September 2016, London.

SCI Cheminformatics for Drug Design: Data, Models and Tools, 12th October 2016, Duxford, UK



Some current jobs being advertised…….

Experienced Computational Chemist, IOTA Pharmaceuticals Ltd, Cambridge, UK.

Senior Software Developer, Chemical Computing Group Inc, Cambridge, UK.

Application Scientist, Chemical Computing Group Inc, UK or Germany.

Senior Scientific Consultant, Cresset Discovery Services, UK.

C++ Software Engineer in Chemoinformatics, Optibrium, Cambridge, UK.