This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff.
Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too.
One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs.
Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier?
Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era.
To me this whole article reads like an advertisement for a screening assay.
I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career.
Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.
Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.
pfisherman|4 months ago
Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too.
One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs.
Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier?
Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era.
To me this whole article reads like an advertisement for a screening assay.
colingauvin|4 months ago
Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.
abhishaike|4 months ago
sure! i cover this in the essay, the purpose of this dataset is not just toxicity, but repurposing also
>toxicity of major metabolites
this is planned (and also explicitly mentioned in the article)
>no need to worry about CYP’s
again, this is about more than just toxicity
>volume of distribution
i suppose, but this feels like a strange point to raise. this dataset doesnt account for a lot of things, no biological dataset does
>advertisement
to some degree: it is! but it is also one that is free for academic usage and the only one of its kind accessible to smaller biopharmas
nerdsniper|4 months ago
Spivak|4 months ago
wizzwizz4|4 months ago
Novartis dataset paper: https://doi.org/10.1038/s41467-023-40064-9
et2o|4 months ago
nextworddev|4 months ago