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Appeal for Help with Aldehyde Oxidase Assay #214

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mattodd opened this issue May 23, 2014 · 14 comments
Closed

Appeal for Help with Aldehyde Oxidase Assay #214

mattodd opened this issue May 23, 2014 · 14 comments

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@mattodd
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mattodd commented May 23, 2014

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
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mattodd commented Jul 1, 2014

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
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drc007 commented Jul 3, 2014

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
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mattodd commented Jul 3, 2014

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
#214 (comment)
.

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
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drc007 commented Jul 8, 2014

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
#214 (comment)
.

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
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mattodd commented Jul 8, 2014

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
#214 (comment)
.

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
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drc007 commented Jul 9, 2014

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
#214 (comment)
.

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
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mattodd commented Jul 9, 2014

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
#214 (comment)
.

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.

@mattodd
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mattodd commented Jul 9, 2014

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

@mattodd
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mattodd commented Jul 31, 2014

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
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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
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mattodd commented Aug 13, 2014

OK, great. Have updated the shortlist: http://malaria.ourexperiment.org/biological_data/10586/Which_Compounds_to_Send_for_Aldehyde_Oxidase_Assay.html

Picture:

ao shortlist 2

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
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mattodd commented Nov 16, 2014

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.

@mattodd mattodd closed this as completed Nov 16, 2014
@drc007
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drc007 commented Nov 17, 2014

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 #214 (comment).

@mattodd
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mattodd commented Nov 17, 2014

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
#214 (comment)
.

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.

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