3 ms·

Can’t access the article, but a few things make me skeptical. They say micromolar (uM) affinity. That is usually not good enough. 10 uM is about the cutoff of

Can’t access the article, but a few things make me skeptical. They say micromolar (uM) affinity. That is usually not good enough. 10 uM is about the cutoff of what you would want in a lead compound - something to be further improved by a medicinal chemist. I suspect they were above 10 uM because if you have low uM affinity you should definitely call it out. They used a pseudo virus but do not say which. They do not tell you which cell line or cell type they used for their disease model. This info should have gone in the abstract. It would not have taken more than a few characters. Basically the quality of the abstract makes me doubt the quality of the research. Also please keep in mind that this is a pseudo virus in a cell model. The graveyard of drugs is filled with filled with compounds that looked good in disease models, but did not work. Generally, the further away you are from a live virus in a live human, the less predictive the model.

refurb 5y ago
Yup. uM activity is crap. We’d discard anything that wasn’t in the nM range. And even then try and optimize. You’d never get those kinds of concentrations in a human (well not never, but you’d be gulping down grams of the stuff if your Vd was good, tens of grams if it wasnt).
- gpcr1949 5y ago
  I think >1 μM activity can be ok depending on what kind of target and what kind of IC50 assay is done. Of course, as you know, comparing IC50s is famously something that cannot/should not be done, because they are assay and condition dependent, even for the same target, which is another reason why a μM cutoff is not set in stone for me. A value like that can be OK when trying to find a (clean, well behaved, synthesizable) early hit for later optimization into an actually useful probe or drug. However, in this case the IC50 are high double digits so I agree you will never get these kind of concentrations in humans without causing problems due to off-target activity.

refurb 5y ago

Yup. uM activity is crap. We’d discard anything that wasn’t in the nM range. And even then try and optimize. You’d never get those kinds of concentrations in a human (well not never, but you’d be gulping down grams of the stuff if your Vd was good, tens of grams if it wasnt).

gpcr1949 5y ago
I think >1 μM activity can be ok depending on what kind of target and what kind of IC50 assay is done. Of course, as you know, comparing IC50s is famously something that cannot/should not be done, because they are assay and condition dependent, even for the same target, which is another reason why a μM cutoff is not set in stone for me. A value like that can be OK when trying to find a (clean, well behaved, synthesizable) early hit for later optimization into an actually useful probe or drug. However, in this case the IC50 are high double digits so I agree you will never get these kind of concentrations in humans without causing problems due to off-target activity.