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Open Source Malaria Webinar recording

OSM-logo@2x

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

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.

Cheminformatics for Drug Design: Data, Models & Tools

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

A4 Cheminfo flyer

Community for Open Antimicrobial Drug Discovery

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

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

You can also read more details in this Nature article DOI

It looks like they have achieved an important milestone!

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

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



Using 3Dmol.js

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.

Predicting sites of metabolism

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

Open Source Malaria online meeting

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)

Pasted Graphic

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,

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.