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Saw this new diabetes drug advertised on TV today, it's structure looks oddly familiar! https://en.wikipedia.org/wiki/Sitagliptin (FDA approved in 2006)
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Matthew Todd's profile photoEgon Willighagen's profile photo
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Matthew Todd
moderator

Meeting  - 
 
Current ppt slide deck for Monday's OSM meeting. Completing the deck tomorrow. Any others?
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Matthew Todd
moderator

Meeting  - 
 
Next Open Source Malaria online meeting is on Monday 27th July. See link below for times. We've an hour to discuss next steps with Series 4. Should anyone else want to discuss anything else of interest to members of the consortium, we should organise other/follow-up meetings, no problem. #medchem #malaria  
Updated due to meeting postponement: Meeting number 10 will happen on Monday July 27th at these times and at this location. The two main items under discussion will be analog design (also #301 ) a...
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Matthew Todd
moderator

Request  - 
 
Request for medchem intuition: what to make next in Series 4. Latest data gave some important negatives, but now we're seeking tractable structures that might be positives... Planning session coming soon so that we can shortlist a Top 10, but in the meantime suggestions welcome. What are we all missing?
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Matthew Todd
moderator

Recent Research  - 
 
Suggestions for next OSM Series 4 analogs from Mrinal Kundu, TCG Life Sciences. Comment here or there if you think these suggestions should be acted upon as replacements for, or in addition to, the current OSM top 10 most desirable compounds. If you'd like to make any of these, there's lots of synthetic precedence: http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Synthetic_Chemistry
Dr Mrinalkanti Kundu, Associate Director TCG Lifesciences, India, wrote to the OSM email address with some new suggestions on which molecules to make next. These suggestions have been adapted from the Christmas Top 10 list as well as all the SAR data on the wiki. Series 4 Suggestions from Mrinal ...
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Ian Kiku

Discussion  - 
 
Help make it happen for 'K.O-Malaria.Smart mobile app to help fight malaria' http://igg.me/p/k-o-malaria-smart-mobile-app-to-help-fight-malaria/x/10404356 #indiegogo via @indiegogo
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Sproxil, Inc.

Discussion  - 
 
Join the discussion about creative solutions to combat malaria with Malaria No More @sproxil& Bliss GVS! http://www.sproxil.com/blog/free-webinar-malaria-no-more-sproxil-and-bliss-gvs/ 
Webinar: Partnering to Combat Malaria April 22, 2015 10:00am - 11:00am EST Webinar link to be provided to registered attendeesWith World Malaria Day (April 25) swiftly approaching, Sproxil, Malaria...
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Matthew Todd
moderator

Recent Research  - 
 
Background on inhibition of ATP4, the proposed target of OSM's Series 4. There is a strikingly broad array of chemotypes that inhibit this target. If we're going to understand this we need to build a pharmacophore model for the Series. This project will start soon, once we've gathered all the data, but this post contains the background. #malaria #medchem #drugdiscovery  
There is evidence from Kiaran Kirk's lab that Series 4 of the OSM Consortium inhibits ATP4, an ion homeostasis pump that has become an important target in antimalarial drug discovery. This importance stems from it being an apparently validated target with a candidate, KAE609, in the clinical ...
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Mandrake Fernflower's profile photo
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This is a bit unrelated, but what software are you using to generate these amazing looking molecule galleries?
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Of interest for the team/collaborators.  I could field comments here or on the blog (but not both please)

http://cdsouthan.blogspot.se/2014/11/pubchem-triage-of-osm-antimalarials-nov.html
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Hamid ahmed elhadi's profile photo
 
As historically man had the wisdom to face health obstacle faced him at where & when no healthcare around , still such wisdom prevailing , with which is more health threats are solved as we do to acute malaria here in Sudan . Guess it worth much to consider for malaria victims welfare  
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About this community

A place to coordinate all activities related to malaria research that are open source: shared resources, data or ideas. Emphasis: primary research, rather than just news.

AdvaCare Pharma

Discussion  - 
 
The First Ever #Malaria   #Vaccine : Is it as Good as Reported?
Leading global health experts look at the pros and cons of using the first, imperfect, malaria vaccine.
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Matthew Todd
moderator

Discussion  - 
 
Summary of what we know of the metabolic liabilities of OSM's Series 4, in advance of the meeting in 10 days. How do we use this information in the next round of analog design? #medchem  
What are the best strategies for minimizing metabolic clearance in OSM Series 4? This has been, and remains, a key scientific issue for us, along with maintaining potency and improving solubility. We're devising the next set of compounds to make (also GHI301) and we're meeting next week (GHI317) ...
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Mandrake Fernflower's profile photoEgon Willighagen's profile photo
7 comments
 
After browsing the vast records of Janssen, I found a possible winner! (The analog is mine, doesn't have anything to do with Janssen, other than copying a certain functional group)
O=C1N(N=NN1CC)CC4=CN=CC3=NN=C(C2=CN=C(OC(F)F)C=C2)N34 logP: 1.72
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Suzanne Catty

Discussion  - 
 
Primary health care
Malaria kills more than 1,500 people in Ethiopia every year. Now a new drug is improving survival rates – and is easy to administer at local village health posts
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Matthew Todd
moderator

Discussion  - 
 
Should we, and can we, buy samples of compounds from CROs in open source drug discovery projects?
Background: http://malaria.ourexperiment.org/the_osm_blog/11562
Github question: https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/292
Feel free to add comments below too.
One of the key issues to solve in open source drug discovery and development programs is how to obtain physical samples of molecules for evaluation. A number of different methods can be envisaged, ranging from direct funding of synthesis (e.g. from grant money, hiring local researchers) through ...
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Mandrake Fernflower's profile photo
2 comments
 
I noticed that when SMART-CYP is ran on the molecule pictured - It lights up like a Christmas tree with metabolism warnings - Any idea on predicted half-life?
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Matthew Todd
moderator

Paper  - 
 
Github repository set up for the writing of the first OSM paper on Series 4. Should allow anyone to contribute directly on that platform, or (more old school) download files, alter them and then ask for them to be uploaded by emailing them to opensourcemalaria@gmail.com. Either way this ought to make the assembly of the paper in a submission-ready form easier, as well as adding robust version control.
OSMSeries4Paper1 - Working Repository of Files Related to Open Source Malaria Series 4, Paper 1
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Matthew Todd
moderator

Request  - 
 
Call for help in synthesising the next most-wanted compounds in OSM Series 4. After much consideration, these are the ones needed. A few milligrams of each are required for biological evaluation. As usual, contribution of samples, and the associated data, makes the contributor eligible for possible inclusion as an author on the resulting paper. The compounds have a lot of synthetic organic precedence behind them and are available in 4 steps from a commercial starting material. #malaria #openscience  
The 'top ten' Series Four compounds have been defined as: I (Alice) will firstly take care of compounds 1 - 4 at Sydney University meaning that we'd like to open up compounds 5 - 10 for synthesis by the community. Two proposed synthetic routes for 5 - 10 could be accessed are: ...
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Mrinalkanti Kundu's profile photoEgon Willighagen's profile photo
 
Greetings!
I have some humble comments on the 'OSM Christmas Top 10 List'.

[i] Comparing head to head MMV 639565  & 670945 with MMV 668959 & 669009 [changing 4-Cl/4-OCHF2-Ph to either THP or N-linked Piperidine], there is a drastic loss in potency; that probably suggests the need of pi-pi interaction/aryl group at that position.

In that context, compounds S, U & W may not be beneficial; moreover, the presence of the -OH group may render metabolic instability as we have seen in MMV 670947 [related].

[ii] Keeping in mind the potency and hERG data MMV 670936, the compound V [From the Top 10 List] looks interesting; though -OH group will probably improve the potency, it may lead to metabolism.

Accordingly, modifying -OH to -OMe may avoid these issue [also we know, -OMe is well tolerated in MMV 669844]. Secondly, 3, 5-di fluorophenyl may be used instead.

Look forward to the feedback.
Best regards.
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Matthew Todd
moderator

Request  - 
 
The OSM Christmas Top 10 list. In the grand tradition of making lists towards year's end, here's the Top 10 List of molecules most needed right now. Any better ideas? Please suggest below. If you'd like to make any of these in the lab, and have the molecules tested, you're free to do so and be included on the paper that will come out of that work.
Which molecules to make next in Open Source Malaria Series 4? The full reasoning is below. The executive summary is that OSM needs these ten molecules: OSM Christmas Top Ten. And if you'd like to synthesise them yourself (open source only please), or suggest better ones, you're free to do so.
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Brian Glanz's profile photoEgon Willighagen's profile photoMarcus Hanwell's profile photoRichard Rose's profile photo
 
Update (April 15th 2015) Jack Ryan (CSIRO, Aus) emailed to "suggest considering the Topliss decision tree strategy for situations with limited throughput in chemistry/biology – see 10.1021/jm00280a002 and 10.1021/jm3011806" - I don't think this is the right route here, but will open a Github issue to collect other opinions (at https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/291). Reply below if you see value in this approach for the above series. What about +NextMove Software 's matched pairs software (10.1021/jm500022q) instead?
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Matthew Todd
moderator

Discussion  - 
 
Gah - more on Chemdraw solubility prediction via LogP and CLogP - obviously depends on which tautomer you draw, but also depends on those explicit/implicit H's on heteroatoms. (Shortcut directly to relevant picture in post: http://malaria.ourexperiment.org/data/files/14206/Tautomers%20and%20CLogP.png) Anyone know to what extent we ought to worry? We're using a predicted logP threshold of about 3. Obviously if we are wrongly calculating logP then we could be designing analogs wrongly. Should we switch to some other resource as standard (ideally one open to the whole community)?
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