Submission of a Review on Antimalarials

[mattodd]

@edwintse and @maratsydney have been reading up on the current malaria pipeline as part of their graduate studies. We had the idea recently of writing up some of this work as a useful, short review - a kind of Field Guide to Malaria Medicines. Ed came up with a really nice way to represent compound data graphically.

Anyway, within a short space of time we had an article that was looking complete. We just polished it a little and are nearly ready to submit. We realize, though, that this paper and its progress has not been shared, which was an oversight. It's not related to any of the Series OSM is looking at. But nevertheless.

So the paper is shared here in its current draft form. We're hoping to submit in the next 1-2 weeks. Any comments gratefully received. Small things or big. There are some little gaps in the compound data (marked with "?") and I intend to ask the relevant groups if they have those data to hand, since we couldn't find them in the lit. The supplementary info spreadsheet is also uploaded.

The emphasis of the paper is to summarize the hit to lead campaigns of the molecules in development. But we also needed to cover past and present medicines briefly to give the context. There's an emphasis on promising mechanisms of action.

It's going to Malaria Journal, and will be open access, obviously. The journal has kindly confirmed that they are fine with us posting it here before submission. ChemRXiv and other preprint servers don't seem to take reviews. So we're using OSM infrastructure (courtesy of Github) to run our own preprint nanoserver.

Ed and Marat have done a cracking job, but please don't hesitate to peer review here. Very happy to acknowledge peer review in the final article.

We were hoping that, following publication, this review could become the basis for a "living review" in a wiki style, i.e. a review that could be updated by the community continuously, perhaps with links to/from the MMV website, but we've not yet had that conversation with MMV or anyone else.

[mattodd]

Update: missing data now summarised as a spreadsheet in the same place, including contact details taken from relevant papers. Will try to reach out to all these authors to pin down any remaining data if they are willing to share. Obviously if other people find these missing data, please say so below by commenting!

[holeung]

Very nicely done! This should be a valuable reference for years to come. I'll take a look at it. Please let me know if there is any way I can help.

[cdsouthan]

Good stuff. While it would have been good to hold a final draft over until Jan 2019 when we could have intersected the ~ 50 structures that will be in the live beta portal for the @GuidetoPHARM Guide to Antimalarial Pharmacology https://www.slideshare.net/cdsouthan/the-iupharmmv-guide-to-malaria-pharmacology-103311134 … . However, I don't think anyone would advise hold things up. The GtoPdb team with Jane Amstrong as the AM project lead will peruse the draft with interest. Actually, it's no bad thing to do this the other way round i.e. we cross-check to see what additional leads we might choose to capture

I hope you are going to add a Figshare link to a supp dat csv file of names to SMILES/InChI and PubChem IDs. If you just have the former but not CIDs we may be able to help.

[mattodd]

Update: Have written to corresponding authors asking for insight into missing data. @cdsouthan yes a suitable and comprehensive mapping would be useful and we could use your help with that.

[cdsouthan]

Best of luck ..... JFTR my colleagues including Michael Spedding and Jane Armstrong were impressed with the draft and the latter is x-checking what we don't have. We hope to synch with our Jan release. I assume the esteemed @edwintse and @maratsydney have ChemDraw files from which they can spawn SMILES and InChIs? Also be interesting to see if MeSH had indexed the lead structures in any of those papers.

[holeung]

Some initial comments:

1. I would like to see more discussion of the potential mechanisms of action and resistance for the two most important drug classes, quinines and artemisinins. More insight into these areas may lead to new, better drugs. In addition, the mechanism of the artemisinins is still a mystery and scientifically intriguing.

2. There are many more active compounds being investigated that work by different mechanisms. For example, there are many protein and lipid kinase inhibitors that are being explored.

I can write something addressing these points if you would like.

[mattodd]

Thanks @holeung

Well, the review is intended to be brief, meaning we're referencing out to larger studies related to MoA and mechanisms of resistance. @edwintse @maratsydney are there significant articles in the last few years that might bolster this part of the review for quin/art, or do you think we're covered?

Re other compounds - we've had to draw a line somewhere, otherwise we'll be discussing a lot of compounds, and we decided the line would be drawn at the clinical phase. So I think we're covering all compounds that have been in a clinical trial of some kind or which are scheduled for a trial. Obviously we link out to the MMV website which has a healthy selection of projects that are in an earlier phase of development. An article describing the landscape of targets that are the subject of more speculative R&D would be interesting, but could constitute an article in itself... Which we could think about.

[mattodd]

Update: have reached out to all people who have not yet responded to our request for data (many have, very kindly and promptly) and we'll give remaining folks till Friday before we go ahead with organising submission. Data may not be available, or people may just be busy. Updated sheet of missing datapoints is available, as well as an updated draft of the review itself. I'll also ping folks at MMV, just to see if they'd like to proof/chip in.

[cdsouthan]

You can put me down as a formally suggested referee if you like. Mind you I think I'll need a beer(s) pledge to get me in a good reviewing mood .....

[MFernflower]

One might question if it would be a good idea to do paper proofreading after a hearty session in the pub

[cdsouthan]

@edwintse @maratsydney do you have the CDX files?

[edwintse]

@cdsouthan Sure do, any in particular?

[cdsouthan]

Not just yet, when my colleague gets round to triaging the paper we can pick up those for code names we don't have structures for.

[cdsouthan]

I've had a much better idea @edwintse - please prepare small data sheet with SMILES (generated from the CDXs) and the names or code numbers in the text. I will intersect these in PubChem and the list could go as Figshare supp dat for the paper?

[drc007]

I'd avoid any binary data format like .cdx, go for an plain text format, SMILES, SDF, MOL etc.

[cdsouthan]

Amen, yes - SMILES should do nicely :) If there any round-tripping issues (almost certain to be a few) these will get picked up during the PubChem mapping

[mattodd]

@cdsouthan @drc007 Just to clarify what you're after here. All compounds in the paper in one chemdraw sheet saved as SDF or something equivalent? Do you want correspondence with compound numbering in the paper? If you can lay it out for us, it'll make it easier to get it right. Going to submit tomorrow, we hope, and we could include this file with the submission (to be posted at the journal) if that is eventually useful.

[cdsouthan]

We (at GtoPdb) would be fine with just a mapping sheet of SMILES against the code numbers (i.e from Fig 6 onward and in bold in the text) All the INN names should map unequivocally into PubChem (on a good day) so we don't need them. (didn't mean to close BTW). If you want to add a complete SDF bundle to Figshare as well that's fine

[mattodd]

Update: review submitted today. Thank you for all your advice and comments. Will let you know how it goes.