OSDDMalaria Agenda, Feb 26th 2013

25 Feb
Published by Alice Williamson

 

 

Our next project meeting of the Open Source Drug Discovery for Malaria consortium will be on Tuesday February 26th at the following times:
 
West Coast US 4 a.m.
East Coast 7 a.m.
UK noon
Geneva 1 pm
Delhi 5:30 pm
Sydney 11 pm
 
To join the meeting and take part, just go here: 
 
http://webconf.ucc.usyd.edu.au/osddmalariafeb262013/

N.B. No password required, just enter as a guest. Some browsers may need adobe add-ins for it to work. 

 
Background Reading:
 
The story so far
http://openwetware.org/wiki/OSDDMalaria:Story_so_far
 
and previous meeting minutes
http://www.thesynapticleap.org/node/438
 
Agenda:
 
1. The near-neighbours
 
 A selection of compounds based on the ‘simplest’ near-neighbour OSM-S-35, (lowest M.W.) have been synthesised:
 
https://plus.google.com/114702323662314783325/posts/2HSmyf2xx68
 
Associated data:
Syntheses: http://malaria.ourexperiment.org/near_neighbours
Activity: http://malaria.ourexperiment.org/biological_data/6734
 
...since these NN compounds were active, but too insoluble. The choice of synthesised compounds was influenced by calculated logP data.
 
http://malaria.ourexperiment.org/biological_data/3160/In_vivo_Plasmodium_Berghei_mouse_trial_of_initial_leads.html
 
No solubility problems with OSM-S-35, an average IC50 of 30 nM (now measured 3 times), good glutathione data however zero effect in mice. 
Previously, an assumption was made that the near neighbours were so insoluble, this would have explained the lack of activity. With the potent new NN compounds we can no longer assume this. 
 
Analysis of potency vs logP for the set:
https://plus.google.com/114702323662314783325/posts/J8LdunS2uQ8
 
2. Glutathione trapping experiments on OSM-S-35
 
In earlier rounds of biological evaluation, the near-neighbours showed extremely high potency. One concern regarding this family of compounds, was their ability to act as Michael acceptors in vivo. A glutathione trapping experiment performed in Sue Charman’s lab suggests that the compounds do not act as Michael acceptors. Do these results validate our continued interest in this family? Should we continue to synthesise analogues? MNR and AEW can highlight current synthetic challenges. Or should we progress one or two more polar compounds into in vivo?
 
Glutathione data
http://malaria.ourexperiment.org/biological_data/6729
 
The NN compounds also showed high potency in a late stage gametocyte assay. Should we re-evaluate some of these in such an assay to confirm their activity?
 
Original gametocyte data:
http://malaria.ourexperiment.org/biological_data/3066
 
3. The Wanted Compounds
 
MNR performed modelling to decide whether further synthetic efforts should be  directed towards the synthesis of some compounds identified at an earlier stage of the project.
 
https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/Xp9mB7icLGF
 
PT has synthesised the sulfonamide, using some procedures developed by MD - currently awaiting biological results.
 
Do we need to synthesise any of the other compounds? The ether?
 
4. Thienopyrimidines and triazoloureas
 
JC and AB have been working on these series. OSM-S-106 has been submitted for biological testing. What does the future hold for these families? Should we synthesise further analogues?
 
5. New families
 
Based on the TCAMS data set, should we be looking at any other families or concentrating on our current targets?
 
6. A.O.B
 
What do we need to do to complete the paper? i.e. how much more investigation of the NN's should we be proposing? What is the status of the paper?
Compound labelling system
Data management - how should we maintain the full spreadsheet of data most effectively, and to what extent do we need to be including e.g. SMILES in every post?
OSDD infrastructure
Expanding the OSDD team
TSL as a hub - do we need to consider alternatives?
Getting more people to be open and interact in the open with results and discussion

Comments

MatTodd's picture

Recording: http://www.youtube.com/watch?v=5XCfDPBxkcg

Minutes and Discussion: http://www.thesynapticleap.org/node/441