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| ''This is a human-readable summary of the 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= |
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| =The story so far in the open source drug discovery for malaria project=
| | [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. |
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| ==History== | | ==History== |
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| Last year [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 - a scheme where funds from an external agency are matched by the Australian Government. This has generated funding from May 2012 for three years.
| | 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. |
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| 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 molecules (the Todd lab's primary responsibility) and evaluating them (with other members of the project). Based on the biological results, analogs are made, or the series might be ditched and another one selected. The first series to be tried is based on an [http://openwetware.org/wiki/OSDDMalaria:GSK_Arylpyrrole_Series arylpyrrole] that was one of the most attractive hits 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.
| | ==Project Structure== |
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| The 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 licence conditions below). The main difference is that 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 better and faster. This was found to be the case in a [http://www.nature.com/nchem/journal/v3/n10/full/nchem.1149.html previous synthetic chemistry project involving the drug praziquantel]. | | 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. |
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| ==Three Rounds of Synthesis and Evaluation==
| | 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]. |
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| [https://plus.google.com/u/0/b/114702323662314783325/115627447826173336765/posts Paul Ylioja] started by resynthesising the two known active compounds from the GSK set (OSM-S-5 and OSM-S-6), plus a few simple derivatives, and [http://www.thesynapticleap.org/node/367 confirming that they were active]. The current list of all the compounds made thus far in this part of the project is kept in [http://bit.ly/OSDDcompounds this spreadsheet]. The [http://malaria.ourexperiment.org/biological_data/month/1325376000 biological evaluation] was carried out by three separate labs ([http://www.discoverybiology.org/team/vicky-avery Vicky Avery], [http://www.bio21.org/group-leaders/bio-chemistry/stuart-ralph Stuart Ralph] and the [http://www.gsk.com/collaborations/tres-cantos.htm original GSK Tres Cantos Lab led by Javier Gamo]) to ensure a solid footing of repeatability. The original compounds contained an ester which was thought likely to hydrolyze ''in vivo'', so various versions of the "lower half" of these leads were also evaluated to check whether the original hits were prodrugs, but all these compounds were found to be inactive. The project champion from MMV, [http://www.mmv.org/about-us/our-team/paul-willis Paul Willis], [http://www.thesynapticleap.org/node/349 recommended] a few "near neighbor" compounds that also looked interesting, and a number of these were made too and evaluated in this first round. One compound, OSM-S-9, was found to be more active than the original GSK hits. [https://plus.google.com/u/0/111817031902595048944/posts Sanjay Batra] came on board the project and his student [https://plus.google.com/u/0/113151089809892205923/posts Soumya] made (and is making)[http://malaria.ourexperiment.org/cdriarylpyrroles some analogs] varying in the position of the fluorine atom, though the activity of those tested to date is low. (Sanjay works at the [http://www.cdriindia.org/analytical.htm CDRI] in Lucknow, India, where [https://plus.google.com/u/0/116616719379353298385/posts Saman Habib] also works - Saman is leading the [http://malaria.osdd.net/ Indian OSDDm project] which will hopefully get started soon). The outcome was that the original hits remained interesting (because of their reasonable potency and logP values) but that highly potent novel antimalarials were also being generated in this class. Thus a [http://www.thesynapticleap.org/node/381 second set of compounds was synthesized and evaluated], giving rise to several new highly potent compounds, one of which (OSM-S-39) displayed a picomolar IC50 value. This is impressive given the small number of compounds made to date, and is testament to the quality of the hits contained in the original GSK set.
| | ==Summary of Experimental Progress to Date== |
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| [[Image:Compounds of Interest in Update.png|thumb|center|500px| '''Original and Representative Potent Compounds in the Arylpyrrole Series]] | | Several [[OpenSourceMalaria:Compound_Series|series of compounds]] have been examined, with the scientific detail being found on those pages. |
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| At this point the decision was taken to take the most promising compounds on to advanced biological evaluation, to see what the promise of this class really is (rather than continue to increase potency through analog synthesis). Evaluations to date are as follows.
| | [[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. |
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| * '''Metabolic and solubility assays''': The two original GSK compounds and six other compounds made in this project were evaluated by [http://www.pharm.monash.edu.au/staff/sacharman.html Sue Charman's lab at Monash]. The raw data are [http://malaria.ourexperiment.org/biological_data/3101 here] and can be discussed [http://www.thesynapticleap.org/node/401 here]. The originals displayed good solubility but moderate degradation rates. The other compounds were degraded more slowly but at a cost of low solubility.
| | 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]. |
| * '''hERG''': One of the original GSK compounds (OSM-S-5) plus one of the most potent novel compounds identified to date (OSM-S-35) were subjected to the [http://malaria.ourexperiment.org/biological_data/2999 hERG assay and passed], perhaps implying that this class of compounds should not exhibit undesirable cardiac side effects. Discussion page [http://www.thesynapticleap.org/node/402 here].
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| * '''Late Stage Gametocyte Assay''': Four of the compounds have also been [http://malaria.ourexperiment.org/biological_data/3066 evaluated in a late stage gametocyte assay] with very interesting results indicating unusually high activity in blocking the transmission of the parasite. The original GSK compound OSM-S-5 was inactive. Discussion page [http://www.thesynapticleap.org/node/403 here].
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| * '''In vivo''': However, the two original GSK compounds as well as one of the most promising novel compounds have been evaluated in mice and found to possess zero oral efficacy (Results available [http://malaria.ourexperiment.org/uri/ed here]). This result taken with all the other biological data requires careful consideration about whether to change the focus of the research to another series or whether to continue to alter the structures of the best compounds to overcome the ''in vivo'' roadblock.
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| Based on these results it was decided to carry out a third round of analog synthesis and evaluation on the arylpyrrole series, with an emphasis on analogs a) with low logP and b) that lack the thiazolidinone heterocycle. A consultation [http://www.thesynapticleap.org/node/412 occurred] asking for suggestions for the ten most appropriate compounds to make, and the ten most interesting for commercial procurement. The final stage of the consultation took place [http://www.youtube.com/watch?v=ooM8kuo14Bg live on the web]. As a result the lists were [http://www.thesynapticleap.org/node/416 finalised]; commercial compounds were ordered and synthesis commenced. In early November, the team received results from the [http://www.thesynapticleap.org/node/430 biological evaluation ] of the commercial compounds and the the synthetic compounds that had been completed, along with some analogues. This set of compounds were found to possess low to negligible levels of activity. This surprised the team but also provided some interesting insights.
| | ==How to Comment on What You're Reading== |
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| Currently (Sept 2012) there remain a few compounds which need synthetic input from any labs interested in contributing. The project has to date had no luck in securing donations of the compounds from commercial suppliers.
| | 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. |
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| ==What Are the Compounds Doing?==
| | 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]. |
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| What might this series of compounds be doing to the parasite to kill it so effectively? It's not clear. The original screens were whole-cell assays, so while it is known that the compounds are effective, it's not known what they are doing in any detail. Iain Wallace from ChEMBL has performed [http://www.thesynapticleap.org/node/387 a prediction] of the biological role of these compounds (as well as predictions for the whole "[http://www.mmv.org/malariabox Malaria Box]", which is a set of compounds MMV are providing to people for antimalarial screening and which are the focus of a [http://www.grandchallenges.org/Explorations/Topics/Pages/AntimalarialCompoundsRound9.aspx current round] of Gates requests for proposals). Iain clustered the compounds as a similarity map, allowing visualization of the correlation between structure and predicted activity. Discussed also [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts/F5B9nA2sJLr here]. One of the predictions was that the compounds hit an enzyme known as DHODH, and GSK are at the time of writing screening some of the project's compounds against this enzyme. These predictions are made using informatics - a comparison of the structures of our compounds with other known compounds that have known activities. The argument is based on extrapolation. To evaluate whether the prediction is correct, a subset of compounds has been sent to [http://chemogenomics.med.utoronto.ca/hiplab/index.php Corey Nislow] at the University of Toronto for screening in a yeast-based assay that does not identify for sure what the compounds are doing (which is very difficult) but provides harder biological evidence for a role.
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| ==How to Obtain Other Compounds==
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| The original compounds from the GSK assay were commercially available, arising from libraries that are provided to larger companies by smaller specialised companies. In a medicinal chemistry project like this one starts with a set of compounds, then one sources further compounds that are similar. Novel compounds need to be made. Other compounds may be available by other means, however. Typically in academia required compounds are made in-house because academia works as a closed system, which is inefficient if relevant compounds exist elsewhere on the planet and can be sourced by other means more quickly. In this project organic synthesis of ''novel compounds'' is currently being performed in Sydney and Lucknow. But for ''known'' compounds the following needs to be done.
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| 1) '''Identification of Commercial Compounds:''' What if some compounds we require are already commercially available? How can these be found? Iain Wallace [http://www.thesynapticleap.org/node/399 was able to do a search] of databases such as eMolecules for relevant compounds above a certain threshold of similarity and filter compounds by supplier, generating the "hitlist" quickly and with no manual human input. These can be converted into spreadhseets for quick visualisation - see [https://plus.google.com/u/0/b/114702323662314783325/115975655197247500095/posts/X2Djh2szx9F here] for examples on Jimmy Cronshaw's series (see below for these).
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| 2) '''Obtaining Commercial Compounds:''' With the compounds identified, the relevant suppliers need to be contacted to ask for donations. That will probably not be trivial since it needs a human interaction. Failing that the compounds can just be bought.
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| 3) '''Identification of Other/academic Compounds:''' What about compounds that could be useful to the project but which are not commercially available, e.g. compounds sitting in academic lab fridges? Some can be found using resources like SciFinder, though these require expensive subscriptions. Many compounds that might be perfect for the project may not even be in the published literature, which is another argument for openness in science.
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| 4) '''Get Other/academic Compounds:''' This will be a case of manual contact with interested groups. [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts/VmPupxxrWEr One such enquiry] has already been submitted, to see what happens. Naturally contributions are rewarded by possible authorship on resulting papers.
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| Ultimately, as a species, we are not very efficient at sharing valuable chemical resources. A user-driven list would be helpful - "I need compound X. I can buy it from you, or you can give it to me, or you can make it for me or with me, but I need the compound in timeframe Y." This is like a [http://intermolecular.wordpress.com/2012/04/20/molecular-craigslist/ Molecular Craigslist], and would reduce some of the supply-demand barriers in chemical research.
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| ==Related Series==
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| The arypyrrole series is the first to be examined. Two other interesting-looking starting points from the GSK set, based on a [http://openwetware.org/wiki/OSDDMalaria:GSK_Triazolourea_Singleton triazolourea] and a [http://openwetware.org/wiki/OSDDMalaria:GSK_Amino-thienopyrimidine_Series thienopyrimidine], are currently being resynthesised by [https://plus.google.com/u/0/b/114702323662314783325/115975655197247500095/posts James Cronshaw] in Sydney to confirm their activity, upon which time it will be necessary to decide which, if either, are to be taken on further. In general a strategy for the project is to decide as early as possible which series are looking attractive biologically, because there are still a lot of leads to pursue. If any of these structures look synthetically attractive to you based on your previous experience, please consider joining the project. Some of these molecules are quite straightforward to make and would be suitable for undergraduate lab classes.
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| ==Comments==
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| Comments and input can be by [http://twitter.com/#!/osddmalaria Twitter], [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts Google+], [http://www.thesynapticleap.org/node/342 The Synaptic Leap] or directly on the relevant [http://malaria.ourexperiment.org/ Electronic Lab Notebooks]. This page also has a "talk" tab for input. Or 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.
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| ==Licence== | | ==Licence== |
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| 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. | | 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. |
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.
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.
