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Cambridge MedChem Consulting

Aldehyde Oxidase

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.

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 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.

opentargets

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.

Modulating PGP levels in the blood brain barrier

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.

Lexiscan

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.

Re-evaluation of the traditional diet-heart hypothesis

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

Fragment Screening at Diamond

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.

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.

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.

webbrowsers

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.

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.

Scinder :- Science introduction robot

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.

0f561064-da50-11e5-9bb5-dad214cd7211

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