Appeal for Help with Aldehyde Oxidase Assay

[mattodd]

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?

[mattodd]

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.

[drc007]

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.

[mattodd]

Oh that would be extraordinarily useful, Chris. Perhaps start with those molecules that have already been through the metabolic stability assays?

http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID

Yes, there should be feedback since we'll be generating more experimental data on this series.

On 3 July 2014 05:37, drc007 notifications@github.com wrote:

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.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-47885968 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

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[drc007]

Hi,

I'm not sure in what format you would like a report in?

Cheers,

Chris On 3 Jul 2014, at 11:28, Mat Todd notifications@github.com wrote:

Oh that would be extraordinarily useful, Chris. Perhaps start with those molecules that have already been through the metabolic stability assays?

http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID

Yes, there should be feedback since we'll be generating more experimental data on this series.

On 3 July 2014 05:37, drc007 notifications@github.com wrote:

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.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-47885968 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

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[mattodd]

That was fast. Well the very best thing with primary data is to post to the ELN, and the most efficient way for that to happen is for the originator of the data to post. It's very easy. We wrote a guide

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 example. If you've not got a Google account, it might be easiest just for us to share one of the OSM Google logins with you so you can post. Just say. We have an account specifically for the ELN, which means we can all edit it, but it's also helpful for individuals to post as themselves since then we can easily find contributions.

So the primary data can be attached as e.g. a PDF, or, better, as any raw data file. Try to insert a back link somewhere to this Github post so things are linked.

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 if, when you create the post, you could create a metadata tag that will make this post stand out from all the others that are more based on synthesis.

Any questions, don't hesitate to ask.

On 8 July 2014 02:23, Chris Swain notifications@github.com wrote:

Hi,

I'm not sure in what format you would like a report in?

Cheers,

Chris On 3 Jul 2014, at 11:28, Mat Todd notifications@github.com wrote:

Oh that would be extraordinarily useful, Chris. Perhaps start with those molecules that have already been through the metabolic stability assays?

http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID

Yes, there should be feedback since we'll be generating more experimental data on this series.

On 3 July 2014 05:37, drc007 notifications@github.com wrote:

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.

— Reply to this email directly or view it on GitHub < https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-47885968>

.

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-48276259 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments.

[drc007]

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 On 8 Jul 2014, at 23:31, Mat Todd notifications@github.com wrote:

That was fast. Well the very best thing with primary data is to post to the ELN, and the most efficient way for that to happen is for the originator of the data to post. It's very easy. We wrote a guide

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 example. If you've not got a Google account, it might be easiest just for us to share one of the OSM Google logins with you so you can post. Just say. We have an account specifically for the ELN, which means we can all edit it, but it's also helpful for individuals to post as themselves since then we can easily find contributions.

So the primary data can be attached as e.g. a PDF, or, better, as any raw data file. Try to insert a back link somewhere to this Github post so things are linked.

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 if, when you create the post, you could create a metadata tag that will make this post stand out from all the others that are more based on synthesis.

Any questions, don't hesitate to ask.

On 8 July 2014 02:23, Chris Swain notifications@github.com wrote:

Hi,

I'm not sure in what format you would like a report in?

Cheers,

Chris On 3 Jul 2014, at 11:28, Mat Todd notifications@github.com wrote:

Oh that would be extraordinarily useful, Chris. Perhaps start with those molecules that have already been through the metabolic stability assays?

http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID

Yes, there should be feedback since we'll be generating more experimental data on this series.

On 3 July 2014 05:37, drc007 notifications@github.com wrote:

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.

— Reply to this email directly or view it on GitHub < https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-47885968>

.

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-48276259 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

[mattodd]

That's fantastic, Chris, how interesting.

Some of the predictions are ON the ring N's - I had naively thought that would mean a carbon next to a ring nitrogen. We would do well to avoid anything benzylic. And the OMe group we're thinking about as a replacement for OCHF2 also introduces a little liability.

Very useful, particularly in comparison with Cyp that suggests AO may be relevant here. Not a lot we can do about the triazolopyrazine core, though, at least in the short term.

On 9 July 2014 06:56, Chris Swain notifications@github.com wrote:

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 On 8 Jul 2014, at 23:31, Mat Todd notifications@github.com wrote:

That was fast. Well the very best thing with primary data is to post to the ELN, and the most efficient way for that to happen is for the originator of the data to post. It's very easy. We wrote a guide

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 example. If you've not got a Google account, it might be easiest just for us to share one of the OSM Google logins with you so you can post. Just say. We have an account specifically for the ELN, which means we can all edit it, but it's also helpful for individuals to post as themselves since then we can easily find contributions.

So the primary data can be attached as e.g. a PDF, or, better, as any raw data file. Try to insert a back link somewhere to this Github post so things are linked.

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 if, when you create the post, you could create a metadata tag that will make this post stand out from all the others that are more based on synthesis.

Any questions, don't hesitate to ask.

On 8 July 2014 02:23, Chris Swain notifications@github.com wrote:

Hi,

I'm not sure in what format you would like a report in?

Cheers,

Chris On 3 Jul 2014, at 11:28, Mat Todd notifications@github.com wrote:

Oh that would be extraordinarily useful, Chris. Perhaps start with those molecules that have already been through the metabolic stability assays?

http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Metabolism_ID

Yes, there should be feedback since we'll be generating more experimental data on this series.

On 3 July 2014 05:37, drc007 notifications@github.com wrote:

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.

— Reply to this email directly or view it on GitHub <

https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-47885968>

.

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

— Reply to this email directly or view it on GitHub < https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-48276259>

.

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-48455821 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

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[mattodd]

By the way am working on sourcing experimental validation of the AO idea - update soon. Pinging @PaulWillisMMV for the above predictive work.

[mattodd]

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 Place your votes!

[PaulWillisMMV]

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

[mattodd]

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 MMV669784 MMV669844 MMV669846 MMV670246 MMV670250 MMV670944 MMV670946 MMV671927 MMV672727 MMV672939

Plus ONE of these two, whichever has the most sample available:

MMV670947 MMV672942

@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?

[mattodd]

Compounds were sent: http://malaria.ourexperiment.org/biological_data/10586 Data were obtained: http://malaria.ourexperiment.org/biological_data/11208 Added links to wiki. Closing this issue.

[drc007]

I get a server not found when I trey to open these links.

Cheers

Chris

On 16 Nov 2014, at 23:12, Mat Todd notifications@github.com wrote:

Compounds were sent: http://malaria.ourexperiment.org/biological_data/10586 http://malaria.ourexperiment.org/biological_data/10586 Data were obtained: http://malaria.ourexperiment.org/biological_data/11208 http://malaria.ourexperiment.org/biological_data/11208 Added links to wiki. Closing this issue.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-63244428.

[mattodd]

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:

I get a server not found when I trey to open these links.

Cheers

Chris

On 16 Nov 2014, at 23:12, Mat Todd notifications@github.com wrote:

Compounds were sent: http://malaria.ourexperiment.org/biological_data/10586 < http://malaria.ourexperiment.org/biological_data/10586> Data were obtained: http://malaria.ourexperiment.org/biological_data/11208 < http://malaria.ourexperiment.org/biological_data/11208> Added links to wiki. Closing this issue.

— Reply to this email directly or view it on GitHub < https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-63244428>.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/214#issuecomment-63291911 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments.