Screen for a potential new series - Orphan Drugs? Is there a library of these?

[PatrickThomson]

Hi folks,

I recently gave a departmental seminar on OSM at Edinburgh and one of the suggestions I got back merits circulation.

Put simply:

There are lots of molecules out there which have been through Phase 1. Blockbuster drugs, generic drugs, orphan drugs, and a LOT that failed Phase 2/3. This gives us a library of (say) 1,000-10,000 compounds, each of which is (reasonably) safe to just eat a pill of and has a known industrial-scale synthesis. We should see if any of these are effective against drug-resistant malarial parasites.

I realise that the original Tres Cantos set probably had, as part of the 2 million compounds, entries for all commercialised drugs developed by GSK - but what about all the other compounds no company would touch with a bargepole for IP reasons - the generics, the competitor leads? The discussion arose because of the already well-known use of antibiotics as antimalarials due to some kind of plasmodium organelle that's bacterial in origin (not a biologist, sorry...)

This is quite tangential to our normal style of discussion but I can't think of a better way to get relevant eyes on the question, so sorry about the spam!

[mattodd]

Don't know - pinging @PaulWillisMMV . Patrick - paste the above into the Open Source Malaria Research community too, and we'll ask around various places. You're essentially asking about drug repositioning/repurposing, but including molecules that may still be under patent, and as you say I'm not sure if this is a pragmatic problem or an IP one (in the sense that if a molecule is sufficiently well protected there may be little point in testing it since it may not be exploitable). (No problem using Github for asking specific questions like this, by the way)

[PaulWillisMMV]

Patrick, Its a nice idea, indeed MMV went through a similar exercise for Malaria a few years ago, including some follow-up screening. At the time we did not identify any suitable compounds.

Obviously the reason for the compound being stopped in development is important, but as you state, many will have acceptable safety margins for the human target. However if the malaria potency is significantly weaker, this will decrease the safety margins by a corresponding amount and could impact on their suitability. The implications of the effect on the human target must also be considered

There are many initiatives to make the IP for such compounds available to the neglected disease community, for example many organizations have signed up to WIPO Re:Search - see http://www.wipo.int/research/en/about/

[sandygiuliani]

Hi there,

I am new to the OSM project, so I am not entirely familiar with what has been done already.

Re drug repositioning, I am currently developing a computational tool to reposition known drugs for parasitic diseases. I am working on schistosomiasis, but I am probably going to include malaria in my validation protocol, so I could share those results if anyone is interested. -> https://github.com/sandygiuliani/drug_repo

One could include phase 1 compounds (or 2 or 3 or just approved drugs) and shortlist compounds that are likely to be active on a malaria target.

Sure, IP is a problem. Do we have some IP expert in the team?

[mattodd]

Hi Sandra - that would be very interesting. Can you just outline your immediate aims (with either schisto or malaria). Is the idea to collate known, validated compounds and to suggest which might be of interest for schisto/malaria? How would the algorithm work? Predicted binding to predicted/known proteins, or pharmacophore similarity? i.e. with a target, or not? (aside - I was involved in the Tropical Disease Initiative's work in this area back in 2009: http://dx.doi.org/10.1038/nbt0409-320). Naturally a very discrete question could be whether any known drugs are likely active against the same target as OSM's Series 4 (http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series), but Patrick's question was much broader than that.

[sandygiuliani]

Hi Matt, the algorithm works by mapping known drugs to their targets to potential parasite targets, via domain architecture matching. In this fashion: known drugs (ChEMBL/DrugBank) ---1---> their targets (UniProt ID) ---2---> domain architectures (CATH/Pfam) ---3---> parasite targets (UniProt ID)

step 1 - all free,available data from ChEMBL or DrugBank. The ChEMBL data can be filtered according to drug type and phase of development (1,2,3 or 4 i.e. marketed drugs) step 2 and 3 - this mapping is built on ArchSchema by Dr Laskowski (http://www.ncbi.nlm.nih.gov/pubmed/20299327)

Please note I am still implementing the algorithm at the moment!

[PaulWillisMMV]

A paper describing MMV's repositioning activities has just been published (Open access, of course) http://www.malariajournal.com/content/13/1/143/abstract

[mattodd]

That's good timing Paul! Sandra - I guess this is an excellent place to start for validation of the approach?

On 6 May 2014 21:00, PaulWillisMMV notifications@github.com wrote:

A paper describing MMV's repositioning activities has just been published (Open access, of course) http://www.malariajournal.com/content/13/1/143/abstract

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[sandygiuliani]

Thanks, I will look into this!

[PatrickThomson]

Closing this because my original question was answered and Sandy's project deserves its own thread for future investigation!

[mattodd]

Fine. To avoid orphaning, I installed this thread on a repositioning page on the wiki http://openwetware.org/wiki/OpenSourceMalaria:Repurposing @sandygiuliani feel free to use this page if it's useful if you start doing something in malaria. Any news on the schisto project, i.e. predictions of something that might be already available?

[sandygiuliani]

Hello! thanks, the Wiki page sounds like a great idea. I am still working on schisto, validation and data analysis are tricky in drug repositioning.. I will keep you posted!