**UPDATE As of 21st Jan 2016 please note the actual structure of BIA 10-2474 changed to this.
To continue the theme of the last few posts on the BIA 10-2474 compound in which I have used over 2000 Bayesian models and an App as well as another groups target prediction tool. To take this a bit further I went to the Click2Drug site to find other examples of software I might be able to use to predict potential interactions for this compound. I tried several of the tools under target prediction that did not require registration.
One of the first I tried was SwissTargetPrediction – this one predicted FAAH as the target and was followed by a list of others such as Sterol O-acyltransferases, histone deacetylases etc.
Another tool called HitPick selected only the serotonin 2A receptor. Several other tools either failed to predict any targets or just seemed to hang. Overall efforts with these tools was pretty disappointing which was unexpected as virtually all of the approaches have resulted in papers.
Next up I went to an old favourite in MetaPrint2D-React to predict sites of metabolism based on a database of known metabolism data for many molecules. David Kroll’s recent blog was concerned about anilines as impurities. When the BIA 10-2474 compound is input (as SMILES) into MetaPrint2D it highlights a red area as being a high probability site of metabolism. If the C=O is dealkylated then it will form an aniline. So could it be possible that the molecule is metabolized to this metabolite and that this is contributing to the toxicity?
Some screenshots of the freely available software is shown below. Certainly there are many other methods that could be used including docking tools, and I have not tried those yet.
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Lauren says:
January 20, 2016 at 9:08 am (UTC -5)
I am unfamiliar with these apps and programs but what happens when you postulate the aniline structure (posing it as the drug) and then ask what is the target? Am expecting it must interact with something local to CNS vasculature.
Ps. As of 2015 toxicities of synthetic cannabinoids have included stroke (hemorrhagic included) with suspicion this is underreported in young people who may have presented in ER.
sean says:
January 20, 2016 at 9:21 am (UTC -5)
Good question Lauren, certainly worth a try. A further question is where is it producing the aniline, liver, brain? With Matthew Krasowski we have previously published on cross reactivity of designer drugs and immunoassays so could possibly compare this compound and see how similar it is to synthetic cannabinoids.
Lauren says:
January 20, 2016 at 10:08 am (UTC -5)
That’s sounds productive. Whatever the causative agent is, it seems to have rather selectively hit brain (vasculature) which is why I posed the receptor based question. If the usual players CYPs etc were at work, it seems aniline would be released in liver site and then the liver/kidney would show up as the most sensitive target. So that’s why I haven’t favored traditional metabolic toxicity.