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Comment by zetalyrae | Hacker News Reader

But viagra has a plausible-sounding (to me, I am not an MD) mechanism of action. Whereas in the first paper[0] about chloroquine for COVID, the claim is:

>This drug has multiple activities, one of which is to alkalise the phagolysosome, which hampers the low-pH-dependent steps of viral replication, including fusion and uncoating. Other mechanisms of antiviral activity are poorly explained.

Which sounds like limited evidence.

[0]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134866/

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> Other mechanisms of antiviral activity are poorly explained.

You would be surprised how many drugs have an unclear mechanism of action. If you think we know everything in Biology you might want to revise your judgment.

Maybe I'm wrong, but I really want to be able to mostly correctly presume that the average HN user over the age of like... 20(?) probably has vague knowledge of the fact we don't understand the mechanism of things like acetaminophen (Tylenol) and most anesthetics...

Furthermore, most chemical engineering/pharmacy students learn that with today's regulations, acetaminophen would've never been approved. Do we think that's a good thing? I don't.

That said, I still very much agree with the parent poster's view.

Anyone that has ever taken a class in molecular biology or biophysics knows that it's ridiculously complex. Many drugs that look promising in vivo or in animals fail to perform in humans. Empirical evidence is what counts. Even targeted enzyme inhibitors are made by a shotgun approach. Synthesize 1000s of candidates and try them all to see which ones work best in vivo and then try those in animals and then try those winners in humans.

That's no reason to try out random drugs, and pick some of those due to noise and artifacts in the tests.

That's pretty much how small-molecule drug development works. They have huge high-throughput screening machines to churn through libraries of millions of chemicals, running assays to see whether they produce the desired results in vitro. Throwing everything at the wall and seeing what sticks.

Once they get hits, they run more big assays, winnowing down likely tox issues or off-target effects, then try them in animal models, then eventually get to Phase I.

That's pretty much how drug development is done, especially at scale. You have robots running tests on hundreds/thousands of molecules in mini-tubes to check if anything has any kind of effect.

Isn't there a huge difference between in vivo and in vitro, though? If it's in vitro, you can actually physically check that it's working, and then rerun it to confirm. If it's in vivo and you're doing an RCT it's much more prone to statistical noise and the other issues, which is why it's bad to try things out randomly and see what sticks. At a test power of 0.05, one in twenty studies will stick due to chance.

It's a selection process. In vitro is for identifying candidates for pre-clinical tests, mostly.

that's the best method we have so far! really. I work in drug discovery.

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