As 2016 ends I'd like to take the chance to wish you all a Happy New Year and hope for great success in your drug discovery endeavours.

This website continues to increase in popularity with over 108,000 page views, an increase of 16% over the figure for 2015. The pages were visited by over 50,000 viewers and around a quarter of the visitors come back on multiple occasions suggesting they find it useful. The visitors come from 160 different countries with the US and UK topping the list.

The most viewed pages were

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

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

Looking at the operating systems 57% are Windows users, 22% Mac users, 10% iOS and 8% Android, Chrome dominates the browser stats (58%) with Safari second (20%) and Firefox third (15%).

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

I've just updated the published fragments page.

We are now starting to see some of the results of the screening of academic projects at the European Lead factory that was initiated in 2013.

Dr Mahlapuu’s group, based at the University of Gothenburg, first identified a new target which could be used to reverse metabolic complications in type 2 diabetes. With the help of the European Lead Factory experts, she then screened the Joint European Compound Library of the then 320,000 industry compounds and identified a set of selective and potent small molecules which interfere with this target.

They have now formed a spinout company to develop these leads. ScandiCure has received 1 MSEK from the 2016 SWElife program to continue the development of first-in-class anti-diabetic drug based on small molecule antagonists of a novel key mediator - serine/threonine protein kinase 25 (STK25).

I've updated the brain penetration page to include data from a recent publication, Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer DOI which discusses the issues with targeting brain and central nervous system cancers.

I've just been browsing through the NAR Database issue whilst the the historical focus was on molecular biology resources the current issue contains over 500 resources that would be of interest to drug discovery. In addition to well known databases like ChEMBL, PubChem BioAssay and RCSB there are many others. A few that caught my eye:

TransportersDB Database of membrane transporters
SureChEMBL Annotated patent database
canSAR Cancer research and drug discovery knowledgebase
iPPI-DB Modulators of protein-protein interactions
Withdrawn Withdrawn drugs
Open Targets platform for therapeutic target identification and validation

The latest news report from the European Lead Factory highlights work targeting antimicrobial resistance in collaboration with Professor Chris Schofield (University of Oxford). The high throughput screen of >300,000 compounds and initial triaging provided 50 qualified hits.

Multiple series of compounds were validated through resynthesis, biochemical and biophysical profiling at the European Screening Centre site in Newhouse, complemented with ligand–protein crystallography and antimicrobial evaluation at University of Oxford

Great to see projects like this move forward, demonstrates how important the ELF is in providing hits for academic groups/small companies.

I've updated the Predicting sites of metabolism page.

What is Wellcome Open Research?

• A platform for Wellcome-funded researchers to rapidly publish any research outputs they wish to share.
• Supports reproducibility and transparency.
• Uses an open research publishing model: immediate publication followed by open invited peer review.
• Includes all supporting data, enabling reanalysis, replication and reuse.

A collection of 47 deprioritised pharmaceutical compounds and up to £5 million is being made available to academic researchers through the latest round of the MRC-Industry Asset Sharing Initiative. The collaboration, between the MRC and six global drug companies, is the largest of its kind in the world.

The list of compounds is available here together with brief description of the molecular target and pharmacology, Safety, Tolerability and toxicity information, and any clinical studies that might have been undertaken.

The latest newsletter from the European Lead Factory has just been published and highlights a number of notable achievements.

As a result of the screening campaigns >3000 qualified hits have been awarded to private and public target owners. 72 public target programmes have been accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners. >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.

There are now 450,000 compounds in the compound library of which 120,000 are novel compound specifically synthesised for the ELF.

You can read more details here https://www.europeanleadfactory.eu/results/

The European Lead Factory is a collaborative public-private partnership aiming to deliver innovative drug discovery starting points. Having established the first European Compound Library and the first European Screening Centre, the EU Lead Factory aims to give free access to up to 500,000 novel compounds, a unique industry-standard uHTS platform, and much more.

We are now starting to see publications describing these endeavours..

https://www.europeanleadfactory.eu/results/publications/scientific-articles/

ChEMBL 22 has been released. ChEMBL is a database of bioactive drug-like small molecules, it contains 2-D structures, calculated properties (e.g. logP, Molecular Weight, Lipinski Parameters, etc.) and abstracted bioactivities (e.g. binding constants, pharmacology and ADMET data).

This version of the database, prepared on 8th August 2016 contains:

• 2,043,051 compound records
• 1,686,695 compounds (of which 1,678,393 have mol files)
• 14,371,219 activities
• 1,246,132 assays
• 11,224 targets
• 65,213 documents

There is more information in the ChEMBL blog post

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 https://www.soci.org/Events/Display-Event?EventCode=FCHEM481

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

The European Lead Factory started work just over 3 years ago and have just released an update on results to date.

The EU Lead Factory is an IMI-funded project that aims to create new chemistry based on crowd-sourced ideas and boost applicants’ drug discovery programmes at no upfront costs

• A Sweden-based start-up company, ScandiCure AB, has been founded based on the results of an EU Lead Factory target programme. ScandiCure is developed with the support and investment of GU Ventures, which is wholly owned by the Swedish State.
• Patents on EU Lead Factory compounds for treatment of multi-resistant bacteria infections and cancer.
• An EU Lead Factory programme accepted by IMI’s ENABLE for preclinical development.
• In vivo proof-of-concept generated with EU Lead Factory compounds.
• 2 PhD thesis enhanced with EU Lead Factory target programme assay development and screening results.
• >35 scientific, peer-reviewed articles, whereof one is the 4th most downloaded article published in Drug Discovery Today in 2015.
• 450,000 compounds in the Joint European Compound Library (JECL), whereof >120,000 of the prospected 200,000 novel screening compounds have been synthesised. 330,000 compounds were selected and assembled from the EFPIA participants’ proprietary compound collections within 6 months of operation.
• Many testimonials of the high quality of the EU Lead Factory output and the JECL compounds. For example, 17/49 EFPIA partner screens have triggered further work.
• 72 public target programmes accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners.
• In total, 2925 qualified hits have been granted public and private target owners (1041 and 1884, respectively).
• >1500 bespoke compounds synthesised in hit validation and hit-to-lead phase of public target programmes.
• >10 crystal structures of target–compound complexes have been solved.
• >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.
• 12/14 of the public target programmes offered to the industry EFPIA participants have been asked to provide a dossier for further assessment.
• >30 academic postdoctoral fellows trained in industry methods and approaches.
• Researchers in 13 countries (BE, DE, DK, ES , FR , IT, IL, HU, NL, PL , PT , SE, UK) involved. Partners spread over 8 countries and target owners over 11.
• 2 Custom-built data management platforms, the Honest Data Broker system developed to enable screening data management and triaging, whilst ensuring confidentiality and patentability; TarosGate2, a chemistry workflow management system with a secure built-in electronic laboratory notebook.

I’ve been involved in a number of screens and we have been very happy with the results, this is a great resource long may it continue.

It is also worth noting that the next submission deadline is 10th October 2016, here is the link for submitting assays for consideration. https://www.europeanleadfactory.eu/how-to-submit/drug-target-assays/

Event	FBLD 2016 (Fragment-based Lead Discovery Conference 2016)
Place	Cambridge, Massachusetts, USA
Dates	9th-12th October 2016
Website	http://www.ysbl.york.ac.uk/fbld/2016/
Poster abstracts	Closing date is 30th September
Event	Fragments 2017 - 6th RSC-BMCS Fragment-based Drug Discovery meeting
Dates	Sunday to Tuesday, 5th to 7th March 2017
Place	Parkhotel Schönbrunn, Vienna, Austria
Websites	http://www.maggichurchouseevents.,co.uk/bmcs
also	http://www.rsc.org/events/detail/23352/fragments-2017-7th-rsc-bmcs-fragment-based-drug-discovery-meeting

I’ve just updated the page on molecular interactions, expanding the section on halogen bonding interactions.

I’ve just updated the page on solubility and added a couple of useful assay references.

Solubility may also have an impact on preclinical assays, limited solubility in preclinical ADMET assays may give a false impression of the compounds profile in in vitro assays. Many of the false positives seen in Fragment-based screening are thought to be due to poor solubility at the high concentrations used in the screen. Perhaps the most important is the impact poor solubility can have on gastrointestinal absorption it may also preclude other routes of administration (intravenous).

TargetValidation.org 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

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 https://www.soci.org/Events/Display-Event?EventCode=FCHEM481

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

I’ve updated the Computational chemistry page to include a recent excellent publication, Open Source Molecular Modeling DOI a review that categorizes, enumerate, and describe available open source software packages for molecular modeling and computational chemistry.

There is also an online database https://opensourcemolecularmodeling.github.io that covers most aspects of computational drug discovery

Methods
Development Activity
Usage Activity
Cheminformatics
Toolkits
Standalone Programs
Graphical Development Environments
Visualization
2D Desktop Applications (Table [2ddesktopviz])
3D Desktop Applications
Web-Based Visualization
QSAR/ADMET Modeling
Descriptor Calculators
Model Building
Model Application
Visualization
Quantum Chemistry
Ab initio Calcuation
Helper Applications
Visualization
Ligand Dynamics and Free Energy Calculations
Simulation Software
Simulation Setup and Analysis
Virtual Screening and Ligand Design
Ligand-Based
Docking and Scoring
Pocket Detection
Ligand Design

Added to Comp Chem Page

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

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

I’ve just updated some of the fragment based screening pages, in particular I’ve updated the section on Published fragment Hits. The database now contains 1216 entries culled from over 240 publications directed at nearly 174 different molecular targets using 26 different detection technologies.

I also noticed that a fragment library I was helped design is now commercially available, The Selcia Fragment Library was designed to have broad applicability and chemical tractability. It is also one of the few libraries where solubility has been confirmed experimentally. The profile of the library is included in the fragment library profiles.

An interesting publication in PLOS Medicine titled “Why Most Clinical Research Is Not Useful” DOI.

John P. A. Ioannidis suggests that a series of features that make clinical research useful can be identified, including those relating to problem base, context placement, information gain, pragmatism, patient centeredness, value for money, feasibility, and transparency and concludes …

Overall, not only are (clinical) most research findings false, but, furthermore, most of the true findings are not useful. Medical interventions should and can result in huge human benefit. It makes no sense to perform clinical research without ensuring clinical utility. Reform and improvement are overdue.

Given the costs involved I suspect this final point may catch the eye.

Reform is needed. Altering our approach could easily produce more clinical research that is useful, at the same or even at a massively reduced cost

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.

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.

Biotechnology Innovation Organisation (BIO) have released the results of a huge study on clinical development success rates.

The study included 9,985 clinical trails and covered a wide number of therapeutic ares including Allergy, Autoimmune, Cardiovascular, Chronic High Prevalence Diseases, Endocrine, Gastroenterology, Hematology, Infectious Disease, Metabolic, Neurology, Oncology, Ophthalmology, Psychiatry, Rare Diseases, Respirator, and Urology.

Key findings from the study include:

• Clinical trial programs that used selection biomarkers saw an overall likelihood of approval (LOA) from Phase I of 25.9%, compared to 8.4% when no selection biomarkers were used.
• The overall LOA from Phase I for all developmental candidates was 9.6%, and 11.9% for all indications outside of Oncology.
• Of the 14 major disease areas studied, Hematology had the highest LOA from Phase I (26.1%) and Oncology had the lowest (5.1%).
• Oncology drugs were approved the fastest of all 14 disease areas.
• Rare disease programs had higher success rates at each phase of development vs. the overall dataset.
• Chronic diseases with high populations had lower LOA from Phase I vs. the overall dataset.
• Phase II clinical programs continue to experience the lowest success rate of the four development phases, with only 30.7% of developmental candidates advancing to Phase III

A webinar describing the work undertaken by the Open Source Malaria Consortium was held on 24th May and a recording of the meeting is now available.

The meeting lasted around 1 hour and be viewed online here

Open Source Malaria (OSM) is aimed at finding new medicines for malaria using open source principles, embodied in the 6 Laws of Open Research. At the moment the majority of work involves the synthesis of analogs of compounds identified by big pharma, with the aim of improving their potency while making the molecules more "druggable", what is known as a "hit-to-lead" campaign.

The questions raised in the webinar are highlighted as “Meeting Discussion Points” on the github page. Please feel free to join in the discussions.

RSC symposium on Late Stage Functionalization for Synthesis and Medicines

Date Monday, 5th December 2016 Place Mathematical Institute, Andrew Wiles Building, Oxford, U Organisers RSC-BMCS (Royal Society of Chemistry – Biological and Medicinal Chemistry Sector)

Late Stage Functionalization (LSF) holds the potential to revolutionise the logic of chemical synthesis and open new ways to prepare novel natural products and medicines. The introduction of important chemical groups for medicinal chemistry in the very last steps of the synthesis through LSF could also dramatically speed up the preparation of NCEs and have a major impact on drug discovery. The availability of new powerful catalytic chemistries showing a high degree of functional group tolerance and that can be performed under mild conditions offer tremendous opportunities for chemists to access new molecules that cannot be made easily by conventional approaches.

A joint meeting Organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group

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

The Drug Discovery Resources pages are intended to act as a resource for scientists undertaking drug discovery, they were initially based on a course I give but have been expanded to give much more detail and to cover subjects not covered in the course. The other advantage of an online resource is that I can include features not possible in static pages.

I had started to include interactive structures a while ago but the problems with java applets and plugins meant I had to abandon that effort. The recent advances in javascript viewers has opened up new possibilities and I've started to reinvestigate more interactive viewers. The initial work uses the fantastic molecule viewer 3Dmol.js developed by David Koes.

3Dmol.js is a modern, object-oriented JavaScript library that uses the latest web technologies to provide interactive, hardware-accelerated three-dimensional representations of molecular data without the need to install browser plugins or Java. 3Dmol.js provides a full featured API for developers as well as a straightforward declarative interface that lets users easily share and embed molecular data in websites.

You can read more about it here DOI.

The first page to include an interactive structure is Aldehyde Oxidase, the PDB structure 4UHW is interesting because it shows the binding of both a substrate and an inhibitor binding at a site remote from the active site.

I hope you find this useful and please feel free to contact me with comments and/or suggestions.

I have updated the drug discovery resources on predicting sites of metabolism, I've added several new tools and web-based resources.

The next strategy meeting for the Open Source Malaria team is on May 24th. This is great chance to find out more about this effort and to look for opportunities where you might be able to contribute

Outline agenda:

• Project background & scientific objectives (5)
• Overview of project information sources - ie what's where (5)
• Data sources & summary of analyses (5-10)
• SAR overview, questions for the audience (20)
• Discussion (10-15)
• Final guidance on what's required from the audience & how to submit your suggestions & what happens next (5)

You can register here https://attendee.gotowebinar.com/register/7722880987090170883 - you need to register in order to receive the link for the meeting itself. Please forward this on to anyone you think might be interested,

I have updated the drug discovery resources page on Aldehyde Oxidase. In particular I have included more detail on the species differences and added the recent X-ray structure of AOX1 with substrate and inhibitor bound.

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 https://vimeo.com/149309356

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.

The brain is protected from xenobiotic agents by the blood-brain barrier (BBB) a network of capilliaries lined by endothetial cells characterised by lack of fenestrations and very tight junctions between the cells. This restricts paracelleular diffusion of molecules, in addition there are a number of active transport mechanisms for transporting molecules into and more abundantly out of the brain. The best understood of the transporters is ABCB1 also known as P-gp, MDR1 (mdr1 in rodents) this transporter is present in the blood-brain barrier, in the gut, on hepatocytes, and the kidney. It is also one of the transporters found to be up-regulated in some drug-resistant tumors and is considered to be one of the major causes of treatment failure.

An interesting publication by Kim and Bynoe in J Clin Invest DOI show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner.

They demonstrate that down modulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models.

A great detective story and also serves to underline the need for all clinical trial data to be published and stored in a publicly accessible format.

Ramsden, of the National Institutes of Health, unearthed raw data from a 40-year-old study, which challenges the dogma that eating vegetable fats instead of animal fats is good for the heart. The study, the largest gold-standard experiment testing that idea, found the opposite, Ramsden and his colleagues reported on Tuesday in BMJ.

http://www.bmj.com/content/353/bmj.i1246

I'm in the process of updating the fragment-based screening section of the Drug Discovery Resources and I came across this news article from the Diamond Light Source is the UK’s synchrotron.

At Diamond beamline I04-1, the full X-ray screening experiment has now been implemented as a highly streamlined process, allowing up to 500 crystals to be soaked and harvested in a day, and collected in 24 hours beamtime. The process covers soaking, harvesting, automatic data collection, and data analysis; and fragment libraries are available, or users can bring their own.

This is available to both academic and commercial users but the application process is different.

If you are interested there is a very useful checklist that should simplify the process.

The facility is based at beamline I04-1 and nearby Lab 36, where the soaking and harvesting is performed.

In practice, the experiment will span a few days and even multiple visits to establish crystals' suitability. Users must generate the crystals in their home lab, and are required to come and perform soaking and harvesting themselves: multi-day Lab Visits will be scheduled separate from normal beamline time. In contrast, users do not need to be present for the X-ray data collection, although they are asked to help monitor (remotely) the automated collection when it occurs. A local contact will be assigned, same as for beamtime.

In practice, the first steps to unsure reproducibility are iterative and require a few dozen crystals, and in difficult cases even several Lab Visits; but associated diffraction testing will be fitted in during the Lab Visit where possible. The final "Full run" soaking and harvesting will be scheduled once the soaking protocol is confirmed (in favourable cases during the same Lab Visit).

Data analysis builds on the existing automatic data processing, and we are developing tools to streamline density interpretation and refinement, analysis and presentation of hit results, and depositing hit structures. Use of these tools is optional, but feedback valued: they will be deployed on Diamond's compute environment as they become available.

The Diamond fragment collection is actively evolving from the original Maybridge fragment collection, on the one hand to eliminate compounds that are poorly soluble, unstable or systematically kill crystals. On the other hand it is being expanded with synthesis-ready compounds.

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

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.

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.

Update

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.

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.

Update

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.

This is the latest project I'm involved with, the idea is a means for scientists working in similar areas of science to find out about each others work, provide introductions that will hopefully lead to collaborations.

The video to support the proposal can be found here https://www.youtube.com/watch?v=joarvBnTQ_k

I have updated the Drug Discovery section on Screening Collection design.

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. https://itunes.apple.com/gb/app/medicinal-chemistry-toolkit/id910073742?mt=8" 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.

The Royal Society of Chemistry celebrates it's 175th anniversary in 2016.

As the oldest chemical society in the world, we're proud to be celebrating our 175th anniversary during 2016. We want to mark this milestone by recognising the rich heritage and community of which we're all a part. We'd also like to acknowledge the important role we all play in contributing to the future of the chemical sciences

I thought I'd contribute to the activities by highlighting "Molecule 175" from various databases.

First up ChemSpider a free chemical structure database supported by the Royal Society of Chemistry providing fast text and structure search access to over 40 million structures from hundreds of data sources. ChemSpider ID 175 refers to acetone, a very important solvent with millions of tonnes produced annually.

Next ChEMBL a database of over 1,7 million small molecules and associated biological activity data. ChEMBL175 is Dexibuprofen, this is the active enantiomer of ibuprofen, a well known non-steroidal anti-inflammatory drug.

Drugbank is a richly annotated database of drug and drug target information. DB00175 is Pravastatin a HMG-CoA reductase inhibitor used as a cholesterol-lowering agent.

Pubchem released in 2004, provides information on the biological activities of small molecules. Pubchem CID175 belongs to acetate, the ionised form of acetic acid, Acetate is the most common building block for biosynthesis.

BindingDB is a public, web-accessible database of measured binding affinities, focusing chiefly on the interactions of protein considered to be drug-targets with small, drug-like molecules. BDBM175 refers to an inhibitor of HIV protease designed to take advantage of the C2 axis of symmetry found for this dimeric protease.

Zinc is a free database of commercially available compounds ideal for virtual screening, entry 175 appears to be a hydrated form of the benzodiazepine Clorazepate.

In the IUPHAR/BPS Guide to PHARMACOLOGY entry 175 is Spiramide, a 5-HT2 antagonist.

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 https://attendee.gotowebinar.com/register/6743114969530154241

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The EFMC Prize for a Young Medicinal Chemist in Industry” was initiated to acknowledge and recognize an outstanding young medicinal chemist (≤ 12 years after PhD) working in industry within Europe. The Prize is given annually and consists of a diploma, € 1.000 and an invitation for a short presentation at an EFMC symposium. Two nominees will also be identified and acknowledged. Nominations should be submitted by the candidate’s supervisor via the submission form on this website and should consist of: • a letter by the supervisor. • a brief CV of the candidate. • abstract of potential oral presentation.

Deadline for submission: January 31, 2016

  “The EFMC Prize for a Young Medicinal Chemist in Academia” was established by the European Federation for Medicinal Chemistry (EFMC) to acknowledge and recognize an outstanding young medicinal chemist (≤ 12 years after PhD) working in academia within Europe. The Prize is given annually and consists of a diploma, € 1.000 and an invitation for a short presentation at an EFMC symposium. Two nominees will also be identified and acknowledged. Applications should be done via the application form on this website and should consist of:

• a one-page letter by the candidate including a short rationale for their application. • one page with his/her 5 most important publications. • a brief CV of the candidate. • abstract of potential oral presentation.

Deadline for submission: January 31, 2016

The winners of both prizes will be invited to give an oral communication at the XXIV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2016), August 28 - September 1, 2016, Manchester, United Kingdom. Please consult the website www.efmc.info for more information on the regulations and the application procedure

The increase in antibiotic resistant bacteria has highlighted the need to target infections with the correct drug. A recent paper ‘Rapid antibiotic resistance predictions from genome sequence data for S. aureus and M. tuberculosis’, by P Bradley, et al. Nature Communications, 21 December 2015 DOI describes a program to identify species and resistance profiles of clinical isolates.

The Mykrobe predictor is designed for use by microbiologists and doctors, providing information needed in order to choose the best treatment. It analyses the whole genome of a bacterial sample, all within a couple of minutes, and predicts which drugs the infection is resistant to. No expertise is needed to run or interpret it, and it works on a standard desktop or laptop.

Supports Illumina sequencing data as standard. Antibiotics supported: Beta-lactams (methicillin, penicillin), quinolones (ciprofloxacin), macrolides/lincosamides (erythromycin, clindamycin), tetracycline, aminoglycosides (gentamicin), glycopeptides (vancomycin), rifampicin, mupirocin, fusidic acid, trimethoprim.

The software is available for download from the Mykrobe website.