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''This is a human-readable summary of the first open source drug discovery for malaria project. A less readable collection of all the relevant data can be found [[OSDDMalaria:GSK_Arylpyrrole_Series|here]].''
=The Story So Far in the Open Source Malaria (OSM) Project=


'''Note: This page is currently (May 2 2012) being built, so some links are missing.'''
[http://opensourcemalaria.org/ The OSM project] is primarily concerned with taking public domain compounds that have shown good activity in killing the malaria parasite in cells and improving the properties of those molecules in order to discover a compound that can enter Phase I clinical trials. This is phenotypic drug discovery project focussed on the hit-to-lead phase. The project operates on open source principles, in that everything is open.
 
=The story so far in the open source drug discovery for malaria project=


==History==
==History==


Last year [http://openwetware.org/wiki/Todd my lab] received seed funding for a pilot project in open source drug discovery from the Medicines for Malaria Venture (MMV). Our project champion at the outset was [http://www.mmv.org/about-us/our-team/tim-wells Tim Wells], who had clearly been thinking along similar lines to me - rather than debate the idea of open source drug discovery any more, let's just try it. [http://www.mmv.org/about-us/our-team/jeremy-burrows Jeremy Burrows] quickly came on board and led the suggestion to go after a few of the actives that had been [http://www.nature.com/nature/journal/v465/n7296/abs/nature09107.html placed in the public domain in 2010] by GlaxoSmithKline and others. We got [http://malaria.ourexperiment.org/tcmdc_ap/1/PaalKnorr_Synthesis_of_1aryl25dimethyl_Pyrrole_Core_PMY_11.html started in the lab] in August 2011. We were [http://sydney.edu.au/research_support/funding/arc/linkage_2012.shtml successful] in securing further funding from an ARC Linkage grant - a scheme where funds from an external agency are matched by the Australian Government. This has given us funding from May 2012 for three years - so we have enough money to drive this project for the moment to see if it works.
In 2011 [http://openwetware.org/wiki/Todd the Todd lab] at The University of Sydney received funding for a pilot project in open source drug discovery from the Medicines for Malaria Venture (MMV). The project champion at the outset was [http://www.mmv.org/about-us/our-team/tim-wells Tim Wells]. [http://www.mmv.org/about-us/our-team/jeremy-burrows Jeremy Burrows] came on board and led the suggestion to go after a few of the actives that had been [http://www.nature.com/nature/journal/v465/n7296/abs/nature09107.html placed in the public domain in 2010] by GlaxoSmithKline and others. Work got [http://malaria.ourexperiment.org/tcmdc_ap/1/PaalKnorr_Synthesis_of_1aryl25dimethyl_Pyrrole_Core_PMY_11.html underway in the lab] in August 2011. The team were [http://sydney.edu.au/research_support/funding/arc/linkage_2012.shtml successful] in securing further funding from an Australian Research Council Linkage grant that has generated funding from May 2012 for three years.
 
Naturally we're all really excited about this. The scientific idea behind the project is familiar medicinal chemistry territory - we need to find a small molecule that is effective for the treatment of malaria, and we will do that by making molecules (my lab's primary responsibility) and evaluating them (with collaborators). Based on those results, we make analogs, or ditch the series and pick another. We started with the [http://openwetware.org/wiki/OSDDMalaria:GSK_Arylpyrrole_Series arylpyrrole series] that was one of the most attractive sets in the [https://www.ebi.ac.uk/chemblntd/#tcams_dataset original GSK dataset], but there are [http://pubs.acs.org/doi/abs/10.1021/ml200135p plenty of other series that are also very attractive] from a medchem perspective.
 
The difference with this project though (as we previously described in the [http://www.thesynapticleap.org/node/343 6 Laws]) is that everything is open, meaning all the experiments go on the web (including the ones that did not turn out well). All the data are available. Anyone can do anything they wish with the compounds, with the proviso we are cited - the licence for the project is CC-BY-3.0, though this is sometimes not yet clear on all the various websites we use. The main difference is that anyone can take part - that people may make molecules, offer guidance and input in other ways that change the direction of the project as it is happening. i.e. rather than releasing all our data at the end of the project we release as the project is happening so that people can really become involved in the research. Thus the iterative cycle of analog synthesis in response to biological data that is normally guided by a kind of medchem intuition is now guided by the intuition of the collective. Similarly, since the biological data are all open too, it should be easier to form an objective assessment of a molecule's performance divorced from the judgement of those closest to the compounds. In the same way that in software development "[http://en.wikipedia.org/wiki/Linus%27_Law with enough eyeballs all bugs are shallow]" we hope that the open nature of the research makes the science better and faster. As it did with our [http://www.nature.com/nchem/journal/v3/n10/full/nchem.1149.html previous synthetic project with praziquantel].
 
==Early Stages of the Project==
 
Paul Ylioja started by resynthesising the two known active compounds from the GSK set, plus a few simple derivatives, and confirming that they were active. The biological evaluation was carried out by three separate labs to ensure we were on a solid footing. Our MMV project champion Paul Willis recommended a few "near neighbor" compounds that also looked interesting, and we made a number of these too, which were again evaluated. Sanjay Batra came on board the project and his student Soumya made some analogs that will be included in our first paper, though their activity is low. Sanjay works at the CDRI in Lucknow, India, where Saman Habib also works - Saman is leading the Indian OSDDm project which will shortly get started. The outcome was that the original hits remained interesting (because of their reasonable potency and logP values) but that we were clearly also generating highly potent novel antimalarials in this class. One compound was coming out picomolar. This is quite impressive given the small number of compounds made to date, and is perhaps testament to the quality of the hits contained in the GSK set.
 
Several compounds have been sent for metabolism assays to Sue Charman's lab at Monash and we are waiting for the results. The two original GSK compounds as well as the highly potent near neighbor X are currently being evaluated in mice. Compound X and Y were recently subjected to the hERG assay and passed, implying that they should not exhibit cardiac side effects. Several of the compounds have also been evaluated in a gametocyte assay with interesting results that may suggest they have activity in blocking the transmission of the parasite.
 
==What Are the Compounds Doing?==
 
What might these compounds be doing? We're not sure. The original screens were whole-cell assays, so while we know they're effective, we don't know what they're doing. Iain Wallace from ChEMBL has done a very neat prediction of these compounds (as well as predictions for the whole malaria box, which is a set of compounds MMV are providing to people for antimalarial screening and which are the focus of a current round of Gates requests for proposals). Iain's able to cluster compounds as a similarity map, which is a neat way of visualizing the correlation between structure and predicted activity. Are these predictions right? We're seeking to examine that by sending a subset of compounds to Corey Nislow at the University of Toronto for examination in a yeast-based assay he's developed.


==How do we Obtain Other Compounds?==
==Project Structure==


The original compounds from the GSK assay were commercially-available. Rather than make compounds that might be sourced by other means, what about obtaining commercially-available compounds of interest from the suppliers, either through purchase or donation? Iain again came to help us with this by finding commercially-available compounds through an emolecules search which looked similar to those we are interested in (actually for a related series, see below). Now we have to see whether we can actually obtain these compounds. It's an interesting conundrum - we know that there are compounds sitting in fridges that are related to our most active antimalarials, and all we need are a few milligrams. How do we get hold of these most efficiently? And what about compounds that are not commercially-available? Are there compounds in academic labs that we could evaluate, such as those from the Roberts lab at Scripps (whom we've contacted). What about compounds that are unpublished, but may be excellent candidates for screening? It would be useful to have a needs-driven marketplace for molecules, like a Molecular Craigslist, but it doesn't really exist.
The scientific idea behind the project is familiar medicinal chemistry methodology - the aim is to find a small molecule that is effective for the treatment of malaria, and that involves generating new molecules and evaluating them. Based on the biological results new analogs might be made or the series might be abandoned and another selected. Decisions to abandon series may be taken early because there are [http://pubs.acs.org/doi/abs/10.1021/ml200135p plenty of other series that are very attractive] from a medchem perspective.


==Related Series==
The crucial difference with this project though (as described in the [http://www.thesynapticleap.org/node/343 6 Laws]) is that everything is open, meaning all the experiments go on the web (including the ones that did not turn out well). All the data are available. Anyone can do anything they wish with the compounds, with the proviso the project is cited (see CC-BY licence conditions below). Anyone can take part - people may make molecules, offer guidance and input in other ways that ''change the direction of the project as it is happening'', i.e. rather than the release of all data at the end of the project, data are released as the project is happening so that people can become genuinely involved in the research. Thus the iterative cycle of analog synthesis in response to biological data that is normally guided by luck and medchem intuition is now guided by the intuition of the collective. Similarly, since the biological data are all open too, it should be easier to form an objective assessment of a molecule's performance divorced from the judgement of those closest to the compounds. In the same way that in software development "[http://en.wikipedia.org/wiki/Linus%27_Law with enough eyeballs all bugs are shallow]" the open nature of the research makes the science faster. This was found to be the case in a [http://www.nature.com/nchem/journal/v3/n10/full/nchem.1149.html previous open source synthetic chemistry project involving the drug praziquantel].


In parallel an Honours student in the lab, Jimmy Cronshaw, has started the synthesis of two other hits from the GSK set, again to confirm activity. He's nearly finished one, and is about to do the difficult part of the other series. Again, these are very attractive hits to be pursuing.
==Summary of Experimental Progress to Date==


==Open Source Drug Discovery More Generally==
Several [[OpenSourceMalaria:Compound_Series|series of compounds]] have been examined, with the scientific detail being found on those pages.


We held an interesting one-day meeting on open source drug discovery for malaria where we discussed general issues surrounding open drug discovery, followed by more specific malaria-related ideas. These talks are gradually going up on YouTube, and they frame many of the issues very well, for example the landscape of drug discovery in neglected diseases, and whether patents are necessary in drug discovery. More coming as and when we can do the annotation properly.
[[OpenSourceMalaria:GSK_Arylpyrrole_Series|Series 1]] was based on an arylpyrrole that was one of the most attractive hits in the [https://www.ebi.ac.uk/chemblntd/#tcams_dataset original GSK dataset]. Ultimately this series was parked because the ester, which was metabolically unstable, could not be replaced with another functional group. A related set of compounds within this series (sometimes also referred to as Series 1a), the "Near Neighbours", displayed high potency but were found to be too insoluble. [[OpenSourceMalaria:GSK_Triazolourea_Singleton|Series 2]], the triazoloureas, appeared promising but there was a suggestion another team were working on this series, so it was parked. [[OpenSourceMalaria:GSK_Amino-thienopyrimidine_Series|Series 3]], the aminothienopyrimidines, is still under current investigation, though the analogs examined to date have been inactive and also suffer from low solubility. The OSM project is currently most active in [[OpenSourceMalaria:Triazolopyrazine (TP) Series| Series 4]], a compounds set that has originated from Pfizer, on which there is a significant quantity of data and which (unlike the previous series) has a suggested mechanism of action.


==How We Run the Project==
The compounds biologically evaluated to date (those assigned OSM codes) can be viewed: [http://malaria.ourexperiment.org/osm_procedures/group/Compound%20List picture list], [https://github.com/OpenSourceMalaria/OSM_compounds .sdf], [http://bit.ly/OSDDcompounds old spreadsheet]. The first 100 compounds were [https://www.ebi.ac.uk/chembl/malaria/doc/inspect/CHEMBL2113921 uploaded to ChEMBL].


The technical background to the project is also interesting, though as with everything in this project we're open to suggestions. We're using Labtrove for recording the raw data in electronic lab notebooks. We're using this site to coordinate and discuss ideas. We're increasingly using Google+ for discussion of small points, and Twitter as a broadcast mechanism for updates. We have not used LinkedIn as much as we did for the praziquantel project. We employ a wiki to host the current description of where the project is at. These sites are all quite intuitive and simple, but all have their limitations.
==How to Comment on What You're Reading==


==Why Take Part?==
Comments/input/questions can be contributed via [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts Google+] either by "+"-ing the project or in the [https://plus.google.com/u/0/communities/105318249049322037798 Open Source Malaria Research Community], directly on the relevant [http://malaria.ourexperiment.org/ Electronic Lab Notebooks], via [https://twitter.com/O_S_M Twitter], [http://facebook.com/OpenSourceMalaria Facebook] or by posting a new Issue to the [https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues?state=open GitHub To Do list]. Much of the older project activity happened on the malaria pages of [http://www.thesynapticleap.org/node/342 The Synaptic Leap]. The page you're reading also has a "talk" tab for input if you would prefer, though there are no notifications active. Alternatively please write your own input somewhere (''e.g.'', your own blog) and link to the project. Anonymity is perfectly acceptable, just less useful. Please avoid email if you can.


What of motivations? Why would people contribute? Partly to solve a problem. Partly to be involved with quality science that is open, and hence subject to the most brutal form of ongoing peer-review. Partly for academic credentials (since we'll soon be publishing a paper). Partly to demonstrate competence. Perhaps a mixture of all these things.
For the full summary of ways to join/interact/contribute, please see the "Join the Team" sheet on the [http://opensourcemalaria.org/# OSM Landing Page].


We're playing with the idea of a competition, though - or rather a prize. While we have certainly led the way to a very promising lead compound, we are acutely aware that there is a long road towards having a compound look sufficiently promising that it moves towards clinical trials. There's a lot of tweaking, and perhaps even the move to another series. Who knows. It's likely we will need a lot more input that we have currently been getting, and so we're playing with whether to launch a prize to stimulate input. It would be a teamless prize, awarded based on performance of individuals within a group where everything is shared. Difficult to judge, difficult to award, and hence worth doing.
==Licence==


A final point - the project is open. We don't own it. It exists in itself and those people most active in the project lead it. If you wish to contribute, in any capacity, please do so. There is no need to "clear" anything with me by email first. It's often the case that I will receive questions/suggestions by email. In the development of Linux, the need for Linus to approve everything caused problems, and the observation that "Linus doesn't scale". Well I don't scale either, so it's more efficient if all our discussions are held publicly. I know that a lot of people don't like this. In science we don't tend to get the idea of "beta testing" something. When data are released in science there is an expectation that the data are correct, and usually accompanied by an explanation. I don't understand this view. I'm comfortable with release of data immediately, and then I'm happy to apply a caution filter that makes me skeptical of things until repeated, or makes me unsurprised when a repeat fails.
The project's licence unless otherwise stated is [http://creativecommons.org/licenses/by/3.0/ CC-BY-3.0] meaning you can use whatever you want for whatever purpose, provided you cite the project.

Latest revision as of 16:29, 20 January 2014

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The Story So Far in the Open Source Malaria (OSM) Project

The OSM project is primarily concerned with taking public domain compounds that have shown good activity in killing the malaria parasite in cells and improving the properties of those molecules in order to discover a compound that can enter Phase I clinical trials. This is phenotypic drug discovery project focussed on the hit-to-lead phase. The project operates on open source principles, in that everything is open.

History

In 2011 the Todd lab at The University of Sydney received funding for a pilot project in open source drug discovery from the Medicines for Malaria Venture (MMV). The project champion at the outset was Tim Wells. Jeremy Burrows came on board and led the suggestion to go after a few of the actives that had been placed in the public domain in 2010 by GlaxoSmithKline and others. Work got underway in the lab in August 2011. The team were successful in securing further funding from an Australian Research Council Linkage grant that has generated funding from May 2012 for three years.

Project Structure

The scientific idea behind the project is familiar medicinal chemistry methodology - the aim is to find a small molecule that is effective for the treatment of malaria, and that involves generating new molecules and evaluating them. Based on the biological results new analogs might be made or the series might be abandoned and another selected. Decisions to abandon series may be taken early because there are plenty of other series that are very attractive from a medchem perspective.

The crucial difference with this project though (as described in the 6 Laws) is that everything is open, meaning all the experiments go on the web (including the ones that did not turn out well). All the data are available. Anyone can do anything they wish with the compounds, with the proviso the project is cited (see CC-BY licence conditions below). Anyone can take part - people may make molecules, offer guidance and input in other ways that change the direction of the project as it is happening, i.e. rather than the release of all data at the end of the project, data are released as the project is happening so that people can become genuinely involved in the research. Thus the iterative cycle of analog synthesis in response to biological data that is normally guided by luck and medchem intuition is now guided by the intuition of the collective. Similarly, since the biological data are all open too, it should be easier to form an objective assessment of a molecule's performance divorced from the judgement of those closest to the compounds. In the same way that in software development "with enough eyeballs all bugs are shallow" the open nature of the research makes the science faster. This was found to be the case in a previous open source synthetic chemistry project involving the drug praziquantel.

Summary of Experimental Progress to Date

Several series of compounds have been examined, with the scientific detail being found on those pages.

Series 1 was based on an arylpyrrole that was one of the most attractive hits in the original GSK dataset. Ultimately this series was parked because the ester, which was metabolically unstable, could not be replaced with another functional group. A related set of compounds within this series (sometimes also referred to as Series 1a), the "Near Neighbours", displayed high potency but were found to be too insoluble. Series 2, the triazoloureas, appeared promising but there was a suggestion another team were working on this series, so it was parked. Series 3, the aminothienopyrimidines, is still under current investigation, though the analogs examined to date have been inactive and also suffer from low solubility. The OSM project is currently most active in Series 4, a compounds set that has originated from Pfizer, on which there is a significant quantity of data and which (unlike the previous series) has a suggested mechanism of action.

The compounds biologically evaluated to date (those assigned OSM codes) can be viewed: picture list, .sdf, old spreadsheet. The first 100 compounds were uploaded to ChEMBL.

How to Comment on What You're Reading

Comments/input/questions can be contributed via Google+ either by "+"-ing the project or in the Open Source Malaria Research Community, directly on the relevant Electronic Lab Notebooks, via Twitter, Facebook or by posting a new Issue to the GitHub To Do list. Much of the older project activity happened on the malaria pages of The Synaptic Leap. The page you're reading also has a "talk" tab for input if you would prefer, though there are no notifications active. Alternatively please write your own input somewhere (e.g., your own blog) and link to the project. Anonymity is perfectly acceptable, just less useful. Please avoid email if you can.

For the full summary of ways to join/interact/contribute, please see the "Join the Team" sheet on the OSM Landing Page.

Licence

The project's licence unless otherwise stated is CC-BY-3.0 meaning you can use whatever you want for whatever purpose, provided you cite the project.

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