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Appeal for Help with Aldehyde Oxidase Assay #214
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Chris Swain of Cambridge Medchem Consulting wrote to alert me to an interesting article on aldehyde oxidase on his blog: http://www.cambridgemedchemconsulting.com/resources/ADME/aldehyde_oxidase.html It's impossible to read this and not think this will apply to Series 4! There's a nice test he refers to from a recent Baran article that describes a quick assay for likely AO oxidation. http://pubs.acs.org/doi/abs/10.1021/jm4017976 as well as an industrial group with the likely capacity to run our compounds in an assay - Pfizer at Groton http://onlinelibrary.wiley.com/doi/10.1177/0091270003260336/abstract Unless anyone has a better suggestion, I will contact. |
I could look at predicting the sites of metabolism using FAME (http://pubs.acs.org/doi/abs/10.1021/ci400503s) a predictive tool developed by Bobby Glen's group at Cambridge. I wrote a review here (http://www.macinchem.org/reviews/fame/fame.php) in which I mention that it might be helpful in identifying non-CYP450 mediated metabolism. I'm sure they would also be interested in any AO metabolism data you generate in order to improve their predictive models. |
Oh that would be extraordinarily useful, Chris. Perhaps start with those http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID Yes, there should be feedback since we'll be generating more experimental On 3 July 2014 05:37, drc007 notifications@github.com wrote:
MATTHEW TODD | Associate Professor THE UNIVERSITY OF SYDNEY CRICOS 00026A |
Hi, I'm not sure in what format you would like a report in? Cheers, Chris
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That was fast. Well the very best thing with primary data is to post to the http://malaria.ourexperiment.org/osm_logos_and_templ/7773 ...that looks long, but isn't. You can post if you've a Google account, for So the primary data can be attached as e.g. a PDF, or, better, as any raw Best place for this post would probably be just in the Series 4 ELN http://malaria.ourexperiment.org/triazolopyrazine_se since we don't have a dedicated place for predictive Met. It'd be useful Any questions, don't hesitate to ask. On 8 July 2014 02:23, Chris Swain notifications@github.com wrote:
MATTHEW TODD | Associate Professor THE UNIVERSITY OF SYDNEY CRICOS 00026A |
Hi, I've published it. http://malaria.ourexperiment.org/triazolopyrazine_se/10460/Predicting_sites_of_metabolism.html Let me know if you would prefer any modifications. Cheers, Chris
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That's fantastic, Chris, how interesting. Some of the predictions are ON the ring N's - I had naively thought that Very useful, particularly in comparison with Cyp that suggests AO may be On 9 July 2014 06:56, Chris Swain notifications@github.com wrote:
MATTHEW TODD | Associate Professor THE UNIVERSITY OF SYDNEY CRICOS 00026A |
By the way am working on sourcing experimental validation of the AO idea - update soon. Pinging @PaulWillisMMV for the above predictive work. |
Scott Obach at Pfizer has agreed to run an AO assay on 6-12 compounds, which is great. We now need to decide which compounds we'd like to send: http://malaria.ourexperiment.org/biological_data/10586 |
I support testing MMV669846 and MMV670250 as variation of the core heterocycle. Also MMV670946 + MMV672727 for the reasons give. I would also add MMV668956 (potency 430nM, 124mg) C1(CN(C1)c1cc(c(cc1)F)F)Oc1cncc2n1c(nn2)c1ccc(cc1)OC(F)F to see if increased steric bulk changes AO metabolism Also MMV669844 (40nM, 41mg) C@H(c1cc(c(cc1)F)F)OC potent, benzyl position blocked for metabolism, does this steric effect influence AO, analogue of compounds we are currently exploring MMV672942 (500nM, only 1 mg left so could be tough to get sufficient) - c1(ccc2n(n1)c(nn2)c1ccc(cc1)OC(F)F)NCCc1ccc(cc1)F another core heterocycle with reasonable potency so could be further optimized if AO advantage |
OK, great. Have updated the shortlist: http://malaria.ourexperiment.org/biological_data/10586/Which_Compounds_to_Send_for_Aldehyde_Oxidase_Assay.html Picture: Therefore codes of compounds to be sent, in order: MMV668956 Plus ONE of these two, whichever has the most sample available: MMV670947 @PaulWillisMMV are you happy to pass this on to SPECS to organise delivery of 2 mg each? Are SPECS happy to accept the conditional request for the last two? I'd like to cap this at 12 compounds - if we include both those final ones we'd be 13. It's unlikely both would have enough sample available. Would it be possible to estimate arrival time at Pfizer, so that I can forewarn Scott and his team to expect delivery? |
Compounds were sent: http://malaria.ourexperiment.org/biological_data/10586 |
I get a server not found when I trey to open these links. Cheers Chris
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Hi Chris - the ELN was down for a moment I think, but should be up now. On 17 November 2014 11:29, Chris Swain notifications@github.com wrote:
MATTHEW TODD | Associate Professor THE UNIVERSITY OF SYDNEY CRICOS 00026A |
We have some evidence that Series 4 may be metabolized by aldehyde oxidase (AO):
http://malaria.ourexperiment.org/biological_data/8464
Can anyone offer to screen some compounds to determine if they are substrates for human, rat or mouse AO – perhaps screening against cytosolic fraction in the presence/absence of an AO inhibitor? Does anyone have suggestions for groups running such assays?
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