The latest update to the Open Targets Platform has been released (18.12).

Centre for Therapeutic Target Validation is a pre competitive public-private venture that aims to provide evidence on the biological validity of therapeutic targets and provide an initial assessment of the likely effectiveness of pharmacological intervention on these targets, using genome-scale experiments and analysis. The platform currently contains 28,931 targets, 3,049,882 associations for 10,053 diseases.

There is an open access portal to the platform here https://www.targetvalidation.org. All data is also available for download https://www.targetvalidation.org/downloads/data.

As in previous years all monies saved for not sending greetings cards will be given to the Multiple Sclerosis Society.

Boehringer Ingelheim have made a new addition to opnMe their portal for free chemical probes.

To foster innovation, we openly share selected molecules with the scientific community to unlock their full potential - all for free, no hidden costs.

The latest addition is a potent Chymase inhibitor, Chymase is a chymotrypsin-like serine protease that is stored in a latent form in the secretory granules of mast cells. Upon stimulation, it is released in its active form into the local tissue, contributing to the activation of TGF-ß, matrix metalloproteases and cytokines.

BI-1942 is a highly potent inhibitor of human chymase (IC50 = 0.4 nM) that can be used to test biological hypotheses involving this target in vitro. With BI-1829 we also offer a structurally close analog that is more than 1000 fold less active (IC50 = 850 nM) and can thus be used as negative control for in vitro studies.

Macrocycles offer a unique opportunity to address some of the more challenging drug targets and I've highlighted this on a couple of pages on the Drug Discovery Resources, here and here.

Macrocycles lie outside the usual "drug space" delineated by the Rule-of-5 and macrocycles can adopt different conformation in various media, hiding polar atoms or forming intramolecular hydrogen bonds, thus retaining good cell permeability and ADME properties

I recently got an email from ChemBridge highlighting a new 11,000 member Macrocyclic Library for screening. The general characteristics of compounds in the ChemBridge Macrocycle Library include:

• Molecular weight range up to 800
• Primary ring size ranging from 11 to 27 atoms
• Heterocyclic primary rings
• Scaffolds with and without peptidic backbone elements as part of the macrocyclic ring
• Scaffolds with and without fused rings as part of the primary macrocyclic ring

As a consultant I perhaps see more instances than most of the problems of reproducing literature studies, and I've highlighted several articles that have raised concerns. In particular, the concerns about antibody selectivity, the problems with irreproducible studies and the need for well characterised chemical probes. The excellent work by Elisabeth Bik 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,

This latest correspondence in Nature highlights some of the issues, "Industry is more alarmed about reproducibility than academia" DOI.

This paragraph I find particularly troubling.

By contrast, academic scientists may be reluctant to devote extra time and effort to confirming research results in case they fail. That would put paid to publication in high-impact journals, damage career opportunities and curtail further funding. Evidence of questionable practices such as selective publishing and cherry-picking of data indicates that rigour is not always a high priority.

 

The post highlighting the RSC MedChem School reminded me that I occasionally get asked to suggest books on Drug Discovery. I've compiled a list of books here, if anyone has suggestions for additions please let me know.

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.

I've tried to support research in the Neglected Tropical Disease area in several ways, I organised a session at the 19th Cambridge MedChem Meeting in 2017 and arranged for the session to be recorded and is now available online and has been watched nearly 300 times.

This is a recording of the Neglected and Tropical Diseases Session at the 19th Cambridge MedChem Meeting, 11-13 September 2017. The speakers are Kelly Chibale (Univ of Capetown), Christoph Boss (Actelion), Rob Young (GlaxoSmithKline), Jonathan Large (LifeArc) and Charles Mowbray (DNDI).

So I was delighted to hear that IUPHAR/BPS Guide to pharmacology database have been funded by MMV to add details of antimalarials to their database.

This link http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=970 gives details of antimalarial targets, including gene name, synonyms and Uniprot ID.

This link http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=999 gives details of antimalarial ligands, including mode of action and properties. For example artemisinin.

I'd urge you have a look and I'm sure they would be happy to hear any suggestions.

I've spent a little time updating the Drug Discovery Resources Section of the website. In particular:

• CYP interactions now includes details of published crystal structures and more information on known inhibitors
• I've added page on CYP1A2 from ChEMBL data and updated the CYP2D6 and CYP3A4 pages
• Updated the page on Aldehyde Oxidase
• Added new examples on the bioisosteres page
• Updated the Published Fragments section, including adding the overlay of all examples of Kinase fragment hits from the PDB.
• Added new examples to the Chemical Probes page
• Included more examples of halogen bonding to the Molecular Interactions page

20th SCI/RSC Medicinal Chemistry Symposium on 8 - 11 September 2019 at Churchill College, Cambridge.

Abstract deadline: Friday 9th November 2018

The organising committee wishes to solicit late-breaking, high impact medicinal chemistry talks to finalise the scientific programme. Potential contributions should be communicated to the secretariat at conferences@soci.org by Friday 9th November 2018. A number of conference places will be reserved for poster presenters and contributions are invited from the whole field of medicinal chemistry. Those presenting a poster may also elect to advertise their poster via oral presentation of a single slide 'flash' poster. Detailed procedures and submission deadlines for poster abstracts will be provided in the second announcement.

More details

Cyclophilin D (CYP D), is a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases) that interconvert the cis and trans isomers of peptide bonds with the amino acid proline. Proteins with prolyl isomerase activity include cyclophilins, FKBPs, and parvulin. Inhibitors of Cyclophilin D have been postulated as potential drugs for a variety of therapeutic targets including anti-viral activity DOI, neurodegenration DOI, Cancer DOI etc.

Until recently work in this area suffered from the lack of high quality, selective inhibitors, the best studied being the immunosuppressants Cyclosporin and Sanglifehrin A.

At the recent Macrocycles 2018 meeting Vicky Steadman described the identification and optimisation of potent and orally available selective Cyclophilin inhibitors, more details have just been published J Med Chem paper DOI.

Let's hope with potent, cell penetrant and orally available tools in hand we can sort out the biology and bring forward a new class of therapeutic agents.

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 (https://reframedb.org) 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.

https://reframedb.org/#/search?query=malaria&type=string

This looks like it will be an invaluable resource.

As mentioned on the Target Validation page, Open Targets is a public-private partnership that uses human genetics and genomics data for systematic drug target identification and prioritisation. The current focus is on oncology, immunology and neurodegeneration. An extension to this will be launched on 18 October 2018.

Open Targets Genetics is a new portal developed by Open Targets, an innovative partnership that brings together expertise from six complementary institutions to systematically identify and prioritise targets from which safe and effective medicines can be developed. The Portal offers three unique features to help you discover new associations between genes, variants, and traits, Gene2Variant analysis pipeline, Fine mapping/ credible set analysis, UK Biobank + GWAS Catalog integration.

More details https://genetics.opentargets.org/docs/open-targets-genetics-infographic.pdf

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 Molecular Interactions page has been updated to include a section on anion-aryl interactions.

Just announced. Open Targets Platform release - 18.08.

In this release there is now data on:

• 21,149 targets
• 10,101 diseases
• 6.5 million pieces of evidence
• 2.9 million associations between targets and diseases

The Open Targets Platform is a comprehensive and robust data integration for access to and visualisation of potential drug targets associated with disease. It brings together multiple data types and aims to assist users to identify and prioritise targets for further investigation. A drug target can be a protein, protein complex or RNA molecule and it’s displayed by its gene name from the Human Gene Nomenclature Committee, HGNC. We integrate all the evidence to the target using Ensembl stable IDs and describe relationships between diseases by mapping them to Experimental Factor Ontology (EFO) terms. The Platform supports workflows starting from a target or disease, and shows the available evidence for target – disease associations. Target and Disease profile pages showing specific information for both target (e.g baseline expression) and disease (e.g. Disease Classification) are also available

A couple of people have asked me how to access the category tags that are attached to news items, the short answer is not easily so I've created a new tab at the top of the page that gives you direct access.

Click on the link and you will get an alphabetical listing of all categories with appropriate links.

It may take a day or so for the new menu bar to appear on all pages.

Clinical trials can be extremely lengthly and there have been many discussions about how to get medicines to patients more efficiently than the seemingly bureaucratic process that is currently in place.

Real-Time Oncology Review Pilot Program is a project to try and reduce the time needed to gain approval.

There are important caveats though.

Submissions to be considered for the RTOR pilot should meet the following criteria:
Drugs likely to demonstrate substantial improvements over available therapy, which may include drugs previously granted Breakthrough Therapy Designation for the same or other indications. Drugs meeting other criteria for other expedited programs (e.g. fast track, priority review) may also be considered. Straight forward study designs, as determined by the review division and the OCE. Studies conducted exclusively outside the United States and adjuvant, neoadjuvant, and prevention studies will be excluded. Endpoints that can be easily interpreted (for example, overall survival in a randomized trial). Supplements with CMC formulation changes and supplements with pharmacology/toxicology data will be excluded. Submissions with greater complexity, including those with companion diagnostics, may also be excluded for the purposes of the pilot program.

The real time review means the FDA can continuously review data as it is produced and give early feedback.

RTOR allows the FDA to review much of the data earlier, before the applicant formally submits the complete application. First, the applicant will present topline data for the FDA to determine whether RTOR would be appropriate for the supplement. If the agency determines RTOR is an appropriate review pathway, the applicant can start sending pre-submission data to the agency, under the original NDA/BLA, 2-4 weeks after all patient data has been entered and locked by the applicant in their database

This sort of process may be ideal for some indications where the trials give clear end points, survival in oncology, clearance of parasite in Malaria or other infectious diseases. Clinical trials for Psychiatric disease, marginal improvements over existing therapy or slowly progressing neurological diseases will probably not be suitable.

Boehringer Ingelheim has added it's well-characterised non-covalent ATP-competitive inhibitor of glycogen synthase kinase (GSK-3) Bi-5521 to its open molecule platform opnMe.com.

opnMe.com, the new open innovation portal of Boehringer Ingelheim, aims to accelerate research initiatives and enable new disease biology in areas of high unmet medical need by sharing well-characterized, best-in-class, pre-clinical tool compounds.

BI-5521 is a potent and selective ATP-competitive small molecule inhibitor of glycogen synthase kinase 3 (GSK-3), GSK-3β (IC50) 1.1 nM, with demonstrated in vivo activity. Rat pharmacokinetics are available, together with an inactive related compound.

Another useful tool for Target Validation.

The full agenda for the Macrocycles 2018 meeting 8th-9th October 2018 is now available and it looks to be a great meeting.

Full details of the meeting and registration is available online here http://www.maggichurchouseevents.co.uk/bmcs/macrocycles_2018-online%20registration.htm.

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.

The first circular for the 20th SCI/RSC Medicinal Chemistry Symposium (aka the Cambridge MedChem Meeting) has been announced. This is also a call for abstracts for both oral and poster submissions. Potential contributions should be communicated to the secretariat at conferences@soci.org by Friday 9th November 2018.

You can download the full details of the meeting here PDF.

A number of outstanding talks have already been confirmed.

Opportunity to apply for a share of up to £20 million to deliver game changing or disruptive innovations with significant potential for impact on the UK economy in partnership with Medicines Discovery Catapult.

More details here

Secure the funding you need to progress your projects towards commercialisation. Use our dedicated grant application team to ensure your submissions stand the best chance of success. Our experienced commercial and scientific teams have connections across industry, academia, finance, government, and research networks – we can help take your projects further towards commercial viability.

I've also compiled a page on Grant funded Research

Today Wellcome announced a new £250m not-for-profit fund: the Wellcome Leap Fund . The Leap Fund will accelerate discovery and innovation, with the aim of delivering breakthroughs over a five- to ten-year horizon.

"We want to take advantage of the surprising, left-field ideas that pose the question 'what if?' and support them in a new way that complements our existing funding structures."

Sounds like the aim is to support more high-risk research.

We don’t expect all projects to succeed, but we think the possibilities are incredibly exciting. And in taking some risks and backing at scale, we think we can deliver transformational developments that will improve people’s lives around the world

Wellcome have also recently announced the Open Research fund

Our new Open Research Fund supports innovative approaches that enable data, code or other research outputs to be discovered, accessed and reused

I've also compiled a page on Grant funded Research

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.

The Protein Data Bank is an absolutely invaluable resource, the PDB is an archive of 3D structural information of proteins, nucleic acids, and bimolecular complex assemblies. However it is much, much more than a simple archive, the submitted structures are curated and annotated to add information about protein ID, sequence information, organism, ligand details etc. This allows users to interrogate the database in many different ways. The database currently holds 141209 entries, with over 10,000 new entries added every year. The vast majority are X-ray crystal structures but there are now over 12,000 NMR derived structures.

The PDB also contains 25626 chemical components - 24007 as free ligands in 106374 PDB file and you can search via a web interface or download the structures in sdf file format. However browsing through the downloaded file it was apparently that macrocycles were not well represented. A discussion with the extraordinarily helpful Rachel Kramer Green at PDB revealed the issue. Basically any ligand containing more that two amino-acids is treated as a protein not a ligand, there are other rules to deal with modified amino-acids etc. but the bottom line is that the only way to get a comprehensive view of macrocycles in the PDB is to download the entire PDB and programmatically by parsing the entire data set.

First we need to decide what size ring constitutes a macrocycle. asking the "internet" failed to produce a definitive answer.

You can read the results and download the script here.

There is also a page that discusses macrocycles in drug discovery.

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 http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm. #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.

SULSA’s Assay Development Fund is actively recruiting innovative molecular targets for which there is a strong rationale for therapeutic potential.

Development of a high-throughput assay provide access to the various drug discovery initiatives that are available to the academic community, i.e. MRC DPFS, Bayer G4Targets, Wellcome Trust translational fund, the European Lead Factory, AZ innovation portal etc.

I've updated the Bioisosteres section adding a few more examples of aryl ring bioisosteres, and I've added CypReact to the predicting metabolism page.

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 http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm. #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.

 

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.

https://a16z.com/2018/04/30/building-therapeutics-startups/

I've made a few additions and updated to the Drug Discovery Resources pages. In particular I've updated the covalent inhibitors page and added additional examples to the molecular interactions page. I've also started updating the ADME section and added a page on half-life and how it might be modulated.

I've updated the molecular interactions page to add more details on halogens.

Halogens are present in around 25% of drugs, calculated using data from Guide to Pharmacology Database and often used as bioisosteric replacements for H, Methyl, OH and NH₂.

Bonds to halogen are significantly weaker than hydrogen bonds but there are many examples in the PDB of carbonyls interacting with halogens with bonds to I, and Br predominating. It is perhaps worth noting that halogens have been introduced into ligands to aid X-ray analysis, but they may also influence binding. Based on the observed bond angles the interaction is between the halogen and pi-cloud of the carbonyl rather than the lone pair with a clear clustering of X--O=C-N dihedral angles of 90° associated with interactions that involve primarily the pi-system of the carbonyl.

Recently Boehringer Ingelheim have decided to provide access to a number of chemical probes.

Two new probes for BRD9 and BRD7/9 have been added.

I've added them to the Chemical Probes page.

The lineup for the RSC-BMCS / RSC-CICAG conference on Artificial Intelligence in Chemistry has been announced.

Twitter hashtag - #RSC_AIChem

09.00 Registration, refreshments, and exhibition
10.00 Presentation title to be confirmed Marwin Segler, Benevolent AI, UK
10.30 Presentation title to be confirmed Nadine Schneider, Novartis, Switzerland
11.00 Refreshments, exhibition and posters
11.30 Keynote: What I learned about machine learning - revisited Bob Sheridan, Merck, USA
12.30 Lunch, posters and exhibition
14.00 Molecular de novo design through deep learning Ola Engkvist, AstraZeneca, Sweden
14.30 Scaling de novo design, from single target to disease portfolio Wilhem van Hoorn, Exscientia, UK
15.00 Refreshments, posters and exhibition
15.30 Investigating clusters in solvent data using K-means Ella Gale, University of Bristol, UK
16.00 Deep learning and chemical data Colin Batchelor, Royal Society of Chemistry, UK
16.30 Automation, analytics and AI Darren Green, Molecular Design UK, RD Platform Technology & Science, GlaxoSmithKline, UK
17.00 Drinks reception
18.00 Close

Register here.

Friday, 15th June 2018, Royal Society of Chemistry at Burlington House, London, UK
Poster closing date is 13th April
Bursary closing date is 3rd May

Take note of the closing dates for abstracts

Applications for oral and poster presentations are welcome. Posters will be displayed throughout the meeting and applicants should indicate whether they wish to be considered for a flash oral presentation when submitting an abstract (two minutes, single slide).The closing dates of 28th February (oral) and 8th August (poster).

PhD Student and Post-Doc Conference Bursaries

Did you know that most BMCS sponsored meetings have a number of bursaries available for PhD and post-doctoral students? Normally up to a value of £250, these awards help to cover registration and travel costs. Preference will be given to members of the RSC (and meeting co-sponsors if applicable), especially those who are selected to give posters.

Macrocycles 2018 meeting #BMCS_Macrocycles

Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK

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.

Full details and application forms are here http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm.

I've updated the Molecular Interactions page expanding the section on hydrogen bonds.

The MycetOS (Mycetoma Open Source) project was launched today by the University of Sydney, Erasmus MC, and the Drugs for Neglected Diseases initiative (DNDi) to use an Open Pharma approach to discover compounds that could lead to new treatments for patients suffering from fungal mycetoma (eumycetoma), a devastating disease for which current treatments are ineffective, expensive, and toxic.

More details here….

Join the discussion https://www.reddit.com/r/OpenSourceMycetoma/

or Twitter https://twitter.com/MycetOS

Files here https://github.com/OpenSourceMycetoma

I've just updated the target validation page, highlighting some of the problems with the use of antibodies.

First announcement for the Macrocycles 2018 meeting #BMCS_Macrocycles

Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK

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.

Applications for oral and poster presentations are welcome. Posters will be displayed throughout the meeting and applicants should indicate whether they wish to be considered for a flash oral presentation when submitting an abstract (two minutes, single slide).The closing dates of 28th February (oral) and 8th August (poster).

Full details and application forms are here http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm.

An interesting review of economic benefits of medical research in the UK.

This briefing summarises a new peer-reviewed study estimating the economic returns generated by public and charitable investment in UK medical research.

Bottom line , Every £1 invested in medical research delivers a return equivalent to around 25p every year, for ever.

Studies have focused on cancer, cardiovascular, musculoskeletal disease and mental health research

MMV welcomes 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 activity against sexual stage V gametocytes and evidence of transmission blocking in SMFA.

2. Compounds with activity against asexual liver and/or blood stages

Novel chemical series with EC50<500nM and which have one or more of the following key features:

• A known, novel mechanism of action;
• An inability to select resistant mutants in vitro;
• Activity at more than one life-cycle stage;
• 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 oral single human dose <500mg or an i.m. dose that can be administered in <1mL and sufficient for up to 3 months’ protection in humans.

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 .

I've just updated the page describing Kinase inhibitors, added more on fragments and selectivity.

We recently heard that Pfizer is leaving the neuroscience therapeutic area, with a resulting loss of around 300 jobs. This is of course bad news for the scientists involved but I hope the work that was undertaken within Pfizer does not disappear. Chemical probes are critical tools in target identification and validation and arguably even more so in neuroscience. I hope that Pfizer consider releasing some of the well characterised molecules as freely accessible chemical probes, especially if they could also offer a similar but inactive molecule as a negative control. Many of the older tool compounds reported in the literature have been shown to have inadequate selectivity which compromises understanding the biology.

There are many important therapeutic targets within neuroscience but our biological understanding is currently inadequate to justify the investment in drug discovery, a selection of well characterised probes may provide the tools to support the necessary basic biological research.

The term "privileged structures" was first coined by Ben Evans DOI who recognised the potential of certain regularly occurring structural motifs as templates for derivatization to discovery novel ligands for binding to proteins. Such motifs are of course distinct from false positives molecules that appear in multiple screens due to assay interferences.

A recent publication describes a related approach looking for multi target ligands, a systematic analysis of currently available X-ray structures for compounds forming complexes with different targets DOI, by using X-ray structures they aim to avoid molecules that might interfere with the assay, some of these ligands were described in the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. This work identified 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity.

I've added this to the Privileged Structures page of the Drug Discovery Resources.

The Drug Discovery Resources website continues to increase in popularity with over 137,000 page views, an increase of 27% over the figure for 2016. The pages were visited by over 71,000 viewers and around a quarter of the visitors come back on multiple occasions suggesting they find it useful. The visitors come from 177 different countries with the US (31%) and UK (15%) topping the list.

The most viewed pages in 2017 were

• Distribution and Plasma Protein Binding
• Lipophilicity
• Calculating Physicochemical Properties
• Molecular Interactions
• Bioisosteres
• Molecular Interactions
• Solvation and desolvation
• Formulation
• Kinase Inhibitors
• Acid Bioisosteres
• Fragment based screening
• Aspartic Acid Protease Inhibitors
• HERG
• CYP Interactions

There have been a number of significant updates to the Drug Discovery Resources this year, in particular Target Validation has been expanded and the section on Chemical Probes given a separate page, highlighting invaluable resources like Probe Miner. Another new addition to the site has been the page on Covalent Inhibitors I got a significant amount of feedback on this page and it was updated several times.

I posted a poll on the website asking how many molecules are usually selected from a virtual screening run?

Some people also emailed me with further information. For companies with large internal physical screening collections, and the ability to cherry pick samples, it effectively costs the same to fill a high density plate (>1000 compounds) as it does to select a handful of compounds. On the other hand if the scientist has to purchase compounds then the logistics and cost become a significant obstacle.

There have been a couple of publications this year describing problems arising from analysis of high-throughput screening data, I've updated the Analysis of high-throughput screening data page to try and highlight some of the issues and strategies.

One of the highlights of the year for me was the 19th RSC / SCI Medicinal Chemistry Symposium (#19thCamMedChem) which took place 10th-13th September 2017 at Churchill College, Cambridge, UK. In particular a session on Neglected and Tropical Diseases, to increase the exposure of the brilliant science undertaken in this important therapeutic area the conference organisers arranged for this to be a live webinar. The session was also recorded and is now available online.

https://youtu.be/XLOCFrjrMEY

This is a recording of the Neglected and Tropical Diseases Session at the 19th Cambridge MedChem Meeting, 11-13 September 2017. The speakers are Kelly Chibale (Univ of Capetown), Christoph Boss (Actelion), Rob Young (GlaxoSmithKline), Jonathan Large (LifeArc) and Charles Mowbray (DNDI). To date this has been watched nearly 250 times.

Please feel free to share. #19thCamMedChem.

The European Lead Factory (ELF) is a collaborative public-private partnership aiming to deliver novel lead molecules for drug discovery programs. When the consortium was formed around 5 years ago there was a lot of scepticism about whether a group of 30 partners rating from large Pharma companies to small academic groups could ever agree on a legal framework that would allow the ELF to function. In a addition, in an industry where confidentiality was critical to maintaining intellectual property the idea that a group of large Pharma companies would share their sample collections often regarded as the "Crown Jewels" seemed impossible. However I was at the European Lead factory Stakeholder Meeting (24-25 April 2017) and it is clear that is has been a success and I've written a summary here.

Interestingly the Books and Grant funding research have seasonal peaks in viewing.

The website was also updated this year to use https rather than http, this involved editing a fair number of of hardcoded URLs. Whilst I don't require any secure transactions it does seem that https offers a level of trust that is beneficial. It seems likely that other web browsers will follow Google's lead and have a popup message when accessing any page using http, I suspect this could rapidly become irritating so I've decided to make the move. You will still able to access using http but I'll be setting up redirects later this week. Hopefully the visitors will not really notice any difference.

Looking at the operating systems 52% are Windows users, 21% Mac users, 10% iOS and 9% Android, Chrome dominates the browser stats (62%) with Safari second (20%) and Firefox third (12%).