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9th July 2014 @ 10:38

FAst MEtabolizer (FAME) (http://dx.doi.org/10.1021/ci400503s) is a collection of random forest models trained on a comprehensive and highly diverse data set of 20,000 small molecules annotated with their experimentally determined sites of metabolism taken from multiple species (rat, dog and human)

Molecules for Metabolism Prediction

To evaluate the ability of FAME to predict sites of metabolism an initial test run was undertaken using three compounds sourced from MMV in the OSM Series 4 (the triazolopyrazines) that previously were sent for metabolism ID testing at Monash University. 

See also

http://malaria.ourexperiment.org/biological_data/8464/post.html

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

The SMILES strings for the above structures were taken from the web page and converted into sdf format using MOE, the structures were then converted to the protonation state expected at physiological pH. They were then individually submitted to FAME using the command and options shown below.

./fame -i /Users/swain/Desktop/MMV/MMV670936.sdf -m all –v

The results were displayed using Jmol, and the screen captured images were then annotated using Pixelmator.

The results are shown below, arrows highlight the sites with the highest probability for metabolism. It should be noted that the numbers are not intended to give any indication of rate of metabolism.

MMV669844

MMV669844 predicted sites of metabloism

MMV669848

MMV669848

MMV670936

MMV670936

I also had a look at using SMARTCyp (http://www.farma.ku.dk/smartcyp/about.php) a method for prediction of which sites in a molecule that are most liable to metabolism by Cytochrome P450. Whilst the predicted sites of metabolism for the side-chains was identical interestingly SMARTCyp did not predict any sites in the triazolopyrazine ring. This may suggest the ring is metabloised by a non-CYP450 mechanism, perhaps Aldehyde Oxidase, a non-NADPH dependent, molybdenum cofactor containing soluble enzyme present in the liver and other tissues.

 

Aldehyde Oxidase: An Enzyme of Emerging Importance in Drug Discovery, J. Med. Chem. 2010, 53, 8441–8460 DOI 


SMILES

 

MMV669844

[C@H](COc1cncc2n1c(nn2)c1ccc(cc1)C#N)(c1cc(c(cc1)F)F)OC

MMV669848

FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CN4CC(C=CC=C5)=C5C4)N32

MMV670936

C(COc1cncc2n1c(nn2)c1cnc(cc1)C(F)(F)F)c1cc(c(cc1)F)F


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