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Cambridge MedChem Consulting

2019 Medicinal Chemistry Residential School

Registration for the RSC 2019 Medicinal Chemistry Residential School is now open, it takes place in Loughborough, UK 2-7 June 2019.

Through an in-depth programme of lectures, case studies and hands-on tutorial sessions, this five-day course strengthens excellence in medicinal chemistry by advancing understanding of the factors governing modern drug discovery. Full details are here.


Make sure that you register for this course as soon as possible to take full advantage of early bird savings. Registration includes attendance at all sessions, refreshments and lunch on each full day – plus a conference dinner with wine on Thursday 6 June.

ReFRAME library as a comprehensive drug repurposing library

This looks a very interesting resource described in a recent publication. The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis DOI.

The ReFRAME collection of 12,000 compounds is a best-in-class drug repurposing library containing nearly all small molecules that have reached clinical development or undergone significant preclinical profiling. The purpose of such a screening collection is to enable rapid testing of compounds with demonstrated safety profiles in new indications, such as neglected or rare diseases, where there is less commercial motivation for expensive research and development.

To date, 12,000 compounds (80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. In addition, an open-access data portal ( has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.

The website can be searched by structure or text string.

For Example searching for Malaria highlights a number of known therapeutic agents.


This looks like it will be an invaluable resource.

Properties of clinical candidates

In an excellent publication "Where do recent small molecule clinical development candidates come from?" DOI, the authors give a detailed description on the development of clinical candidates from the initial hit. They also define the changes in physicochemical properties.

An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = −0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex.

I thought it might be interesting to look at the calculated properties of the 66 clinical candidates. Interestingly many have molecular weights > 500 and only around 30% contain an ionisable group. All structures contain an aromatic ring and 48 molecules contain 3 or more aromatic rings.


In case anyone was wondering the high molecular weight compounds are not peptides or macrocycles.

The Polypharmacology Browser PPB2

Off-target activity is often ignored and might only be uncovered relatively late in the drug discovery program. Whilst broad spectrum screening is available it can be rather expensive. Predicting potential off-target activities is an attractive approach and this paper describes the development of a prediction tool using nearest neighbours combined with machine learning.

The Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning DOI

To build PPB2 we collected a bioactivity dataset of all compounds having at least IC50 < 10 uM on a single protein target in ChEMBL22 considering only high confidence data points as annotated in ChEMBL and only targets for which at least 10 compounds were documented

You can try it out here PPB2., depending on the model chosen the results are calculated in a couple of minutes, but don't post your proprietary molecules. Typical results are shown below, clicking on the green "Show NN" button shows the most similar structures.


How reliable is the literature?

In the past I've mentioned some of the concerns about antibody selectivity, the problems with irreproducible studies and the need for well characterised chemical probes. Elisabeth Bik has been looking at concerns with some of the images in the published literature, The prevalence of inappropriate image duplication in biomedical research publications. mBio 7(3):e00809-16. DOI. her Twitter feed contains yet more examples from the current literature, well worth a browse.

So completing this set, I looked at 101 papers, all published in the same month in the same journal. Of these, 63 contained photographic images (the others had only line graphs and/or tables). Of those, 8 have potential duplications. That is 12.7%

With all the advances in AI and image recognition I'm slightly disappointed that there is not a programme that can do this automatically for Elisabeth.

Macrocycles in Drug Discovery

I've created a new page in the Drug Discovery Resources section describing the use of macrocycles in drug discovery. With the advent of more challenging drug discovery targets such as protein-protein interactions there is renewed interest in molecules that are beyond the "Rule of 5". Macrocycles despite apparently undesirable physicochemical properties (High MWt, polar surface area etc.) can have good cell penetration and oral bioavailability.


There is also an upcoming meeting on Macrocycles, 3rd RSC BMCS Medicinal Chemistry Symposium on Macrocycles. Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK. Full details are here #BMCS_Macrocycles

The objective of this symposium is to promote scientific interaction between scientists with a shared interest in the field of Macrocycles. This area is responsible for a growing number of therapeutic approaches and development candidates, all of which go ‘beyond the rule-of–five’. As a researcher in this field, come along to hear about the latest advances and also to share in some of the secrets of discovering therapeutic agents which go beyond Lipinski’s rules.

Pitfalls to avoid when building a Computational Therapeutics Company


Everyday I seem to hear about another tech company moving into healthcare, whilst I'm certain that Artificial Intelligence and Machine Learning has the potential to make a significant impact this advice should be compulsory reading for all involved.

Updated bioisosteres pages

Bioisosteres are an essential tool in the medicinal chemistry toolkit.

Bioisosteres are chemical substituents or groups with similar steric or electrostatic properties which produce broadly similar biological properties to another chemical compound.

Bioisosteres won't always give improved properties, and sometimes we find that a transformation that improves metabolic stability in one series might have the reverse effect in another. However they provide useful (literature precedented) starting points for structural transformations that allow exploration of structure activity relationships. Sometimes they yield similar activity but offer alternative structural vectors for exploration, sometimes they simply improve solubility.


I've now updated the bioisosteres section of the Drug Discovery Resources including new examples people have kindly sent to me.

Computational Tools Updated

I've updated the computational tools page in the Drug Discovery Resources.

First Disclosures at ACS San Francisco

The ACS session organised by Division of Medicinal Chemistry includes a day of first disclosures of potential clinical candidates for the first time. Beth Halford was there and tweeted a series of hands drawn structures as they were disclosed. I've redrawn the structures and converted them into a single sdf file. I've also used Jupyter Notebook to calculate the physicochemical properties and plot them as shown in the image below.


As can be seen, many of the compounds are on the large size with molecular weights >450, a third of them have ionisable groups which serves to bring down the calculated LogD. All molecules contain an aromatic ring, indeed many contain multiple rings. Interestingly we see a number of examples where a biphenyl ring system bears multiple ortho substituents presumably locking the two aryl rings orthogonal, no mention of atrope isomers though. This might also reduce the planarity and increase the 3D shape.

The sdf file is available here if anyone spots any errors in the structures please let me know.

Drug Discovery Resources Updates

I've been updating the Drug Discovery Resources section.

In particular I've added a section on target prediction tools, updated the section on Analysis of HTS data, and expanded the section on aggregation in bioassays to include a recent publication giving an example of target specific aggregation.

The crystal structure showing the interaction is available (PDB 5MU8) and is displayed below using 3Dmol.js, the ligand (JNJ525) is shown in red..

Mouse Controls

Movement      Mouse Input      Touch Input
Rotation Primary Mouse Button Single touch
Translation Middle Mouse Button or Ctrl+Primary Triple touch
Zoom Scroll Wheel or Second Mouse Button or Shift+Primary Pinch (double touch)
Slab Ctrl+Second Not Available

In addition I've updated the section on molecular interactions.

The BMCS Mastering MedChem III: 3rd RSC-BMCS symposium on mastering medicinal chemistry

This meeting is aimed at all those who wish to become better drug hunters and heed warnings from the past. (22 March 2017 09:00-19:00, Cardiff Bay, United Kingdom).

In the main there are two types of drug discovery programmes: those that hit serious problems and those that are going to hit serious problems. The difference between success and failure is how we, as medicinal chemists, tackle and resolve the problems

Sounds a great meeting both for those starting out in their careers and for those looking to pick up new tips.

Drug Discovery Resources Site Update

I've completed a few updates to the Drug Discovery Resources website, this includes fixing any broken links that people have mentioned to me, and also starting a new section in the Pre-clinical toxicity on Mutagenicity.

Cheminformatics for Drug Design: Data, Models & Tools

Still a few places left at the Cheminformatics for Drug Design: Data, Models & Tools meeting organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group has been extended.

Imperial War Museum, Duxford, UK Wednesday 12 October 2016

Full details are available here

Sounds an excellent meeting and you will have a chance to look around the aircraft at the Duxford Imperial War Museum.

Target Valaidation site update has been updated.

This release brings new web displays and plenty of extra data to assist you in drug discovery and validation:

  • 30,591 targets
  • 9,425 diseases
  • 4.8 million evidence
  • 2.4 million target-disease associations

There are also new Web Widgets for both 'RNA baseline expression' and 'Protein Structure' of a target. In the latter, you can now rotate the protein structure, change its colour, zoom in and out, and highlight any amino acid residue:

More information is available on the blog

Cheminformatics for Drug Design: Data, Models & Tools

I’ve just heard that the poster deadline for the Cheminformatics for Drug Design: Data, Models & Tools meeting organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group has been extended.

Imperial War Museum, Duxford, UK Wednesday 12 October 2016

Full details are available here

Sounds an excellent meeting and you will have a chance to look around the aircraft at the Duxford Imperial War Museum.

19th RSC/SCI Medicinal Chemistry Symposium

I’m delighted to highlight the first announcement of the 19th RSC/SCI Medicinal Chemistry Symposium to be held in Cambridge in September 2017. Europe’s premier biennial Medicinal Chemistry event, focusing on first disclosures and new strategies in medicinal chemistry.


Click here for more details

Solutions for Drug-Resistant Infections Meeting

SDRI 2017 is a multi-disciplinary scientific conference for the Asia Pacific region focused on Solutions for Drug Resistant Infections. This inaugural conference theme is New Drugs for Drug-Resistant Infections. The conference will take place at the Brisbane Convention and Exhibition Centre in Australia from 3 - 5 April, 2017.

The program is expected to attract 400 international participants and will provide a fantastic forum for researchers and industry representatives working in the space of microbiology, virology, parasitology, genomics, pharmacology and medicinal chemistry, to network and discuss new ways to solve the global challenge of drug-resistant infections. Our goal for SDRI 2017 is to lead a concerted discussion to set three priorities and guide research efforts towards global solutions for drug resistance research.

Conference themes:

  • Antimicrobial drug discovery
  • Improvements to existing anti-infective agents and repurposing
  • New Drug Targets
  • Alternate therapies
  • Navigating the pipeline
  • International Models and Funding
  • Vector control and vaccines

International keynote speakers confirmed:

  • Professor Dame Sally Davies DBE FMedSci FRS, Chief Medical Officer for England
  • Professor Ramanan Laxminarayan, Director for Center for Disease Dynamics, Economics & Policy (CDDEP), Washington and Vice-President for Research & Policy at Public Health Foundation of India (PHFI)

More details and registration

CO-ADD web portal

The CO-ADD web portal is now live You can now submit your free antimicrobial screening request, download all forms and access your primary screening, cytotoxicity, hit confirmation and hit validation reports online on the new secure CO-ADD user portal.

CO-ADD (Community for Open Antimicrobial Drug Discovery) is a not-for-profit initiative led by academics at The University of Queensland. Our goal is to screen compounds for antimicrobial activity for academic research groups for free. We aim to help researchers worldwide to find new, diverse compounds to combat drug-resistant infections.

Chemical Probes Portal Updated

The Chemical Probes Portal has been updated, the new site includes a lot more data about the existing probes, reviewer ratings and their comments.

A chemical probe is simply a reagent—a selective small-molecule modulator of a protein’s function—that allows the user to ask mechanistic and phenotypic questions about its molecular target in cell-based and/or animal studies. These are tools not drugs, they allow scientists to investigate the relationship between a molecular target and the broader biological consequences of modulating that target in cells or organisms. In general the focus is on specificity for the target rather than pharmacokinetics.

Community for Open Antimicrobial Drug Discovery

A little while ago I mentioned The Community for Open Antimicrobial Drug Discovery effort to provide free compound screening against a variety of infective agents. .

Primary Screening of a 1mg sample Test against key ESKAPE pathogens, E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus (MRSA), as well as the fungi C. neoformans and C. albicans, at a single concentration.
Hit Confirmation:- Confirm activity with minimum inhibitory concentration and counterscreen for cytotoxicity and membrane interaction.
Hit Validation:- Test the positive hit against a broader panel of microbes and evaluate the basic drug qualities of actives. CO-ADD will screen your compounds for free and make no claim to IP. The linked flyer gives full details

You can also read more details in this Nature article DOI

It looks like they have achieved an important milestone!

Thanks to our research community we have received 100,000 compounds from 30 countries in 15 months! Make a difference: clear the fridge, empty the shelves and send through your compounds for free antimicrobial screening against 5 bacteria and 2 fungi. We would also like to acknowledge the contribution of the French National Chemical Library that has safely arrived in Brisbane last week!

So if you have compounds sitting in the back of cupboards why not send them to be tested

Open Targets

A little while back I mentioned the Centre for Therapeutic Target Validation, well it seems that it has now been renamed Open Targets.

The Target Validation platform brings together information on the relationships between potential drug targets and diseases. The core concept is to identify evidence of an association between a target and disease from various data types. A target can be a protein, protein complex or RNA molecule, but we integrate evidence through the gene that codes for the target. In the same way, we describe diseases through a structure of relationships called the Experimental Factor Ontology (EFO) that allows us to bring together evidence across different but related diseases.

There is a video online describing it in more details

This is an absolutely invaluable resource for anyone involved in drug discovery, simply type your query into the text box and submit the query.


This update also bring programmatic access to the data via a series of REST services, the API is fully documented. All the methods are available via a GET request and will serve the output formatted as json. There is a getting started tutorial available.

Unlocking Finance for Drug Discovery

This looks like an interesting meeting for those looking for funding drug discovery

This event is aimed at early and mid-career scientists who are looking to learn more about funding early stage drug discovery or how to attract follow-on investment. A panel of experts, representing several investors from the industry and charities will share their experience and engage in a discussion on the future of drug discovery landscape. Find out about what propels a drug discovery project to secure funding and investment

Location: Cancer Research UK Cambridge Institute Lecture Theatre, Cambridge Biomedical Campus, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE
Date:21 April 2016

Medicines for Malaria Venture 14th call for proposals

MMV have just announced a call for proposals in the following three areas:

  1. Compounds addressing the key priorities of the malaria eradication agenda. Novel families of molecules in the hit-to-lead or lead optimization stages are sought without G6PD deficiency liabilities that either kill or reactivate hypnozoites for use as part of a P. vivax radical cure; or have dual activity against asexual and sexual stages (gametocytes) for treatment and transmission blocking.

  2. Asexual liver and blood stages. Novel chemical series with EC50<500nM and which have one or more of the following key features: A novel mechanism of action A long half-life (ideally >4h in rodents) and confirmed in vivo efficacy. For advanced series, we are seeking novel compounds with, ideally, a predicted human half-life >100h and a predicted single human dose <500mg or three day human dose of <50 mg.

  3. Novel approaches for screening. To help identify new phenotypic and/ or target based hits, as well as confirm activity of MMV compounds on all human malaria asexual blood stages, new screening proposals are sought.

They have also published Target product profiles & target candidate profiles.

Web browsers used in Drug Discovery

Last week I posted this observation

More and more of the companies/groups that I'm working with are moving away from desktop applications to providing a web-based portfolio of applications for drug discovery. Most seem to use a combination of commercial tools with a selection of in house apps. Whilst this has many advantages it does raise the question about which web browser should they support? Whilst NetMarketshare still has Internet Explorer at 44% this is probably not a good metric to measure browser usage in the Drug Discovery Sector. So for the last couple of months I've been monitoring the web browsers used to access the Drug Discovery Resources since it is unlikely that anyone not interested in drug discovery would spend much time browsing these pages. The results are interesting.

The ranking since 1 Jan 2016 to date is

  1. Chrome 55%
  2. Safari 20%
  3. Firefox 16%
  4. Internet Explorer 4%

Looking at operating systems

  1. Windows 57%
  2. Macintosh 23%
  3. iOS 11%
  4. Android 8%

So the lack users of Internet Explorer is not due to the absence of Windows users. This must have implications for all developers, the users appeared to have moved to the more modern web browsers.


I've now data from around 10 different sites involved in drug discovery or software/databases to support drug discovery, ranging from small sites with about 10,000 hits a month to major sites with many millions of hits a month, and I've now included the average data in the table below.


It looks like the data from Drug Discovery Resources reasonably reflects the usage in the Drug Discovery sector.

Web-based tools

More and more of the companies/groups that I'm working with are moving away from desktop applications to providing a web-based portfolio of applications for drug discovery. Most seem to use a combination of commercial tools with a selection of in house apps. Whilst this has many advantages it does raise the question about which web browser should they support? Whilst NetMarketshare still has Internet Explorer at 44% this is probably not a good metric to measure browser usage in the Drug Discovery Sector.

So for the last couple of months I've been monitoring the web browsers used to access the Drug Discovery Resources since it is unlikely that anyone not interested in drug discovery would spend much time browsing these pages. The results are interesting.

The ranking since 1 Jan 2016 to date is

  1. Chrome 56%
  2. Safari 20%
  3. Firefox 16%
  4. Internet Explorer 4%

Looking at operating systems

  1. Windows 57%
  2. Macintosh 23%
  3. iOS 11%
  4. Android 8%

So the lack users of Internet Explorer is not due to the absence of Windows users. This must have implications for all developers, the users appeared to have moved to the more modern web browsers.


A number of readers/companies have contacted me since I published with broadly similar results, I hope to compile and publish the anonymised results next week.

Global Health Compound Design Webinar - recording & next meetings

During 2016 Global Health are running a series of webinars on the subject of compound design. The programme for future meetings is available below (the agenda will develop through the year).

Date Agenda (& timing of each item in the recording when available)

21st Jan 2016

Introduction to meetings, Mark Gardner Application of PK Tools in the optimisation of a series for the treatment of leishmaniasis, Gavin Whitlock, Sandexis, working with DNDi Hints and tips to working with DataWarrior, Isabelle Giraud, Actelion, slides Isabelle Giraud, DataWarrior demonstration" Recording

25th Feb 2016

Visceral leishmaniasis TCP & screen sequence, Charlie Mowbrary, DNDi Malaria Target Candidate Profiles, stage gates and implications for successful malaria drug discovery, Paul Willis, MMV Registration

17th Mar 2016 "DataWarrior advanced data analysis, Isabelle Giraud, Actelion Using the RSC Medicinal Chemistry Toolkit in Drug Discovery Projects, Andy Davis, AZ The RSC Medicinal Chemistry Toolkit is a free suite of resources to support the day-to-day work of drug discovery scientists.  It was developed to provide difficult-to-access, but industry-validated tools in a portable format. The presentation  will show with worked examples,  how the RSC Medicinal Chemistry Toolkit (Apple only) can be used to  support design strategy thinking and structure-activity optimization." Registration

21st Apr 2016

Free data pipelining tool KNIME in compound design & analysis Introduction to KNIME & use cases in drug discovery – further details tbd Registration

There are more details here.

Free webinar to discuss compound design.

Webinar to discuss compound design. This meeting:
* Brief introduction - Mark Gardner (AMG Consultants)
* Application of PK Tools in the optimisation of a series for the treatment of leishmaniasis, Gavin Whitlock, Sandexis, working with DNDi.
* Hints and tips to working with DataWarrior, Isabelle Giraud, Actelion

Register here

Insects in Drug Discovery

The company N2MO offers the use of insects as model organisms. They can be used for ADME screening in particular brain penetration studies.

The Grasshopper: A Novel Model for Assessing Vertebrate Brain UptakeOlga Andersson, Steen Honoré Hansen, Karin Hellman, Line Rørbæk Olsen, Gunnar Andersson, Lassina Badolo, Niels Svenstrup, and Peter Aadal Nielsen EntomoPharm R&D, Medicon Village, Lund, Sweden (O.A., K.H., G.A., P.A.N.); Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (S.H.H., L.R.O.); and Division of Discovery Chemistry and Drug Metabolism and Pharmacokinetics, H. Lundbeck A/S, Copenhagen, Denmark (L.B., N.S.) Received April 10, 2013; accepted May 10, 2013

ABSTRACT The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict.

Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented.

This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtainedinvertebrates.Moreover,this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates.


I've expended the preclinical toxicity section to include a page on hepatotoxicity. This gives some details of the common assays and markers used to evaluate the potential hepatotoxicity.

Time Dependent Inhibition

I've just updated the Drug Discovery Resources page on CYP Interactions, included a section on Time Dependent Inhibition (TDI).


p>The Metabolism and Transport Database (Metrabase) is a cheminformatics and bioinformatics resource that contains curated data related to human small molecule metabolism and transport, Journal of Cheminformatics 2015, 7:31 DOI. Currently it includes interaction data on 20 transporters, 3438 molecules and 11649 interaction records manually abstracted from 1211 literature references and supplemented with data from other resources as shown in the image below taken from the original publication.


I've added this and more details to the Transporters page of the Drug Discovery Resources

Grant Funding Research

I've just updated the page listing possible sources of grant funding for drug discovery research. In particular I've extended the listing of disease specific resources, these may be particularly useful for rare or neglected diseases.

Lack of reproducibility with antibodies

A slightly worrying article in Nature, Reproducibility crisis: Blame it on the antibodies.

The lack of reproducibility of published data on potential drug targets has been highlighted on several occasions DOI and it has been suggested that this is a major factor in the failure rate for phase 2 clinical trials DOI.

In almost two-thirds of the projects, there were inconsistencies between published data and in-house data that either considerably prolonged the duration of the target validation process or, in most cases, resulted in termination of the projects.

Antibodies have rapidly become a key tool in understanding and identifying new drug targets and potentially used as biomarkers to identify patients. However it is clear that many of the 2 million commercially available antibodies need to be checked rigorously, with some scientists claiming more than half are unreliable.

In 2011, an evaluation4 of 246 antibodies used in epigenetic studies found that one-quarter failed tests for specificity, meaning that they often bound to more than one target. Four antibodies were perfectly specific — but to the wrong target.

Caveat emptor.

Medicinal Chemistry Toolkit app

A review of the Medicinal Chemistry Toolkit app for iOS

Free Compound Screening for antimicrobial activity

The concerns about antibiotic resistance are well known and indeed have made headlines in the mainstream press. Here is a chance to help find the next generation of antibiotics.

Do you have interesting compounds sitting on the shelf? Perhaps you would be interested in having them screened for antibiotic activity for free?

The Community for Open Antimicrobial Drug Discovery would like to hear from you, their goal is to screen compounds from academic research groups from anywhere in the world for free.

The requirements are pretty minimal

We ask for 1-2 mg of pure compound which will be used for primary screening, hit confirmation, and if active will be used for a broader antimicrobial screening, cytotoxicity and a check for its purity. We require all compounds to be soluble in water or DMSO and to be shipped as dry material in appropriate containers, such as 1-2 mL Eppendorf tubes. For larger collections we can arrange plates or tube-racks.

In the primary screen they test against against key ESKAPE pathogens, E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus (MRSA), as well as the fungi C. neoformans and C. albicans. The ‘ESKAPE’ pathogens that are responsible for two-thirds of all health care-associated infections and resistant strains of these bacteria represent the greatest unmet need in antibacterial drug development.

Annual Site Review

At the end of each year I take the opportunity to look at the website analytics to see what parts of the website are the most popular. Overall there was a 15% increase in the number of page views up to 75,000. Average time on a page was 2 mins suggesting the content is engaging with the viewers.

Nine of the top ten most popular pages were from the Drug Discovery Resources Pages which I am delighted to see, since it suggests that the work entailed in putting the resources together is worthwhile.

The most viewed pages were

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.

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 updated the Drug Discovery Resources, in particular I’ve updated the section on Brain Penetration to include more on predictive models.


I’ve also updated the page on Grant Funding Research.

Worth a look.

The a third edition of the popular book, The Organic Chemistry of Drug Design and Drug Action by Silverman and Holladay has just been released, I’ve added it to the book list.

Vortex users might be interested in a new script that implements an interesting paper from Wagner et al Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties DOI that describes an algorithm to score compounds with respect to CNS penetration.

Lilly MedChem rules can now be installed using Homebrew. In late 2012 Robert Bruns and Ian Watson published a paper entitled Rules for Identifying Potentially Reactive or Promiscuous Compounds DOI. This article describes a set of 275 rules, developed over an 18-year period, used to identify compounds that may interfere with biological assays, allowing their removal from screening sets.

Drug Discovery Resources Updates

I’ve made a couple of updates to the Drug Discovery Resources pages. In particular I’ve updated the Published fragments Hits to include more examples, details of “promiscuous” compounds and summary of detection technologies and the targets explored. I’ve also updated the Aspartic Protease inhibitors page.

As ever comments and/or suggestions very welcome.

Bringing Open Source to Drug Discovery demo

I spoke at the 25th Symposium on Medicinal Chemistry in Eastern England yesterday and gave a talk/demo on integrating Open Source software into Drug Discovery. I’ve now recorded the demo I showed and put it on YouTube

If you want any further information I’d be happy to try and help.

Bringing Open Source to Drug Discovery

I spoke at the 25th Symposium on Medicinal Chemistry in Eastern England yesterday and gave a talk/demo on integrating Open Source software into Drug Discovery. As I promised at the meeting I’ve published the slide deck that now includes 25 pages on links and resources that I hope you will find useful.

Bringing Open Source to Drug Discovery

If you want any further information I’d be happy to try and help.

The origin of the pharmacophore concept.

Any medicinal chemist will use the term “pharmacophore” to describe key features of a ligand binding interaction in 3D, but have you ever wondered where this important concept originated? Thanks to some detective work by Osman F. Güner and J. Phillip Bowen we now have a better idea who the concept originated and evolved. It is all described in a paper in J Chem. Inf. Model DOI.

The IUPAC defines a pharmacophore to be "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response”.

It is important to recognise that whilst a specific group of atoms may be used to define a pharmacophoric feature, the steric and electronic requirements can be mimicked by a completely different group of atoms.

Kinase Inhibitors

I’ve updated the Drug Discovery Resources to include a page on Kinase Inhibitors. I will be expanding it over the next week, so any comments or suggestions welcome.

Centre for Therapeutic Target Validation

Target validation is the most critical step in drug discovery because as the chemists will tell you “Most of the other things we can fix”, so I was delighted to hear about the new Centre for Therapeutic Target Validation.

You can read more about it in the Press release

”The Centre for Therapeutic Target Validation is a transformative collaboration to improve the process of discovering new medicines,” says Dr Birney. “The pre-competitive nature of the centre is critical: the collaboration of EMBL-EBI and the Sanger Institute with GSK allows us to make the most of commercial R&D practice, but the data and information will be available to everyone. It is truly exciting to apply so many different areas of expertise, from data integration to genomics, to the challenge of creating better medicines.”

I wish them every success and will be following their work closely.

Drug Discovery Resources Update

I’m in the process of updating the drug discovery resources pages.

I’ve added a couple more examples to the bioisosteres pages and revamped the Computational Chemistry Tools page.

I’ve also updated the Journal RSS feeds and included the feed for Chemical Biology and Drug Design.

Open Source Drug Discovery

If you have ever wondered how Open Source Drug Discovery might work there is a very nice example on the Intermolecular blog here.

Well worth a read.

Published Fragment hits

Whilst there are a variety of techniques to measure the properties or diversity of fragment libraries it is interesting to look at the profiles of compounds that actually appear as hits in fragment-based screening campaigns. I’ve been compiling a database of compounds that have been reported as hits in the literature, this database now has >500 entries culled from 150 publications directed at nearly 100 different molecular targets using 18 different detection technologies and might be expected to give some insight into the type of compounds that appear as hits.

You can read more here.

Suggested Books

I’ve just updated the list of suggested books.

Included books on bioisosteres and fragment-based screening.

17th RSC/SCI Medicinal Chemistry Symposium

The registrations are coming in for the forthcoming 17th RSC/SCI Medicinal Chemistry Symposium to be held in Cambridge UK (8-11 Sept 2013). Book early to avoid disappointment.


Full details of the scientific programme are available here together with the registration form.

SMARTCyp 2.4 released

The new SMARTCyp version 2.4 includes solvent accessible surface area (SASA) in the scoring function. SASA is computed using the 2DSASA algorithm from 2D coordinates.


  A paper describing the new models and their predictive accuracy on nine CYP isoforms is available in Molecular Pharmaceutics DOI

Building a Screening Collection

I’ve just updated the page on building a screening collection and added links to recent useful publications.

Broad Coverage of Commercially Available Lead-like Screening Space with Fewer than 350,000 Compounds, Jonathan Baell DOI
Metal Impurities Cause False Positives in High-Throughput Screening Campaigns, Johannes C. Hermann et al DOI

Drug Discovery Resources Update

I’ve updated the Drug Discovery Resources Pages over the Christmas Break. In particular I’ve updated the Fragment Based Screening section and added a page on building a fragment collection. I’ve also updated the section on CYP interactions, expanding the Induction section.

SMARTCyp Updated

SMARTCyp 2.3 has been released with some additional improvements including: Improved energies for N-oxidations Empirical correction for unlikely N-oxidations of tertiary alkylamines A filtering functionality for excluding compounds with very low activation barriers to CYP-mediated oxidations A smiles string can now be input directly on the command line using the -smiles flag.   Available as usual at   The science behind the improved N-oxidations and the empirical correction has also been published in a paper in Angewandte Chemie: DOI  

Modelling the Drug Discovery Pipeline

An interesting publication in the latest issue of Journal of Cheminformatics in which Melvin Yu uses Monte Carlo simulations to look at the Drug Discovery pipeline DOI. With any analysis of this kind it is easy to argue that it is too simplistic however it does raise some useful discussion points. In particular, the idea that simply attempting to improve drug discovery productivity by simply increasing the size of existing working groups may not necessarily be the best solution.

This also sounds familiar

Simulations also predict that the frequency of compounds to successfully pass the candidate selection milestone as a function of time will be irregular, with projects entering preclinical development in clusters marked by periods of low apparent productivity

Perhaps a greater number of independent smaller research units is a more attractive model?


FiercePharma are obviously on a recruitment drive, I have to confess I’m already a subscriber. Makes an interesting read over the early morning cup of coffee.

Viewing docking results in Vortex

This may be of interest.

I recently wrote a review of ForgeV10 from Cresset in which I actually imported the results into Vortex to do the analysis. There were however two issues with doing this, firstly interpretation of the 3D structures is sometimes difficult, this can be resolved by creating a 2D rendering of the structure. The other issue is trying to interpret the docking pose whilst looking at the analysis of the results in say a Vortex scatter plot.

I’ve been working with Mike Hartshorn and the people at Dotmatics who have incorporated OpenAstexViewer (a 3D molecule viewer) into the application you can read the full article here..

Drug Discovery Stage Definitions

I’ve just added a page on Drug Discovery Stage Definitions

Whilst the Drug Discovery process is continuous and can vary depending on target it is often useful to split the process into stages with key milestones and targets clearly defined and met before a project moves from one stage to the next.

ODDT Publication

There is a paper describing ODDT Open Drug Discovery Teams app.

Investigators of rare and neglected diseases can access some of the latest research in the field, plus data about the disorders themselves, through a recently launched free app for Apple devices.

Magic methyl

I’m sure many of us have come across instances where introduction of a single methyl group results in an unexpected increase in affinity. If you have you might like this paper in J Med Chem.

Methyl Effects on Protein–Ligand Binding

Cheryl S. Leung, Siegfried S. F. Leung, Julian Tirado-Rives, and William L. Jorgensen
A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event….The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

DOI: 10.1021/jm3003697

ODDT Released

Open Drug Discovery Teams (ODDT) is now available on the iTunes Store.

The idea behind ODDT is that there are many rare of neglected diseases that might benefit from collaborative efforts from scientists from multiple disciplines, ODDT is an application that supports informal interactions, provides a means to explore relevant information in a flipboard like interface in particular information tagged by other scientists with similar interests. The image below gives you an idea of the topics currently discussed.


This slideshow explains the genesis of the project, and how it has evolved.

So why not fire up iTunes and download the free app and get involved?

Idiosyncratic toxicity

I’ve updated the section on idiosyncratic toxicity to include more information on risk assessment strategies and the influence of clinical dose.

Fragment Collections

I’ve just completed an addition to the Drug Discovery Resources, since fragment-based screening has increased in popularity I thought I’d have a look at available fragment collections. In particular, I looked at the overlap between collections, the physicochemical profiles and their diversity.

Full details are on the Fragment Collection Profiles page.

ChemSpider Search

If like me you regularly come across drugs mentioned on web pages that you are unfamiliar with then this Safari Extension will be of interest. If a page contains a drug name (this page describes AOX1 substrates), select the name and right click (or control click) and an option appears to search for the highlighted drug on ChemSpider.

Click on Search for “Loratidine” on ChemSpider option and the structure appears in a small window.

The new version of the extension has a few extra options, the small window that pops up containing the structure now has a number of additional options highlighted below, if you click on the “3D” button the display changes to a 3D rendering using the Java applet JMOL. If you now click on the “Zoom” button.

If you then click on the “view” option a new page opens showing the full details in ChemSpider.

Updated Pages

Updated the Chemical Databases and Physicochemical Properties pages of the Drug Discovery Resources.

Site Updates

Details of Website updates