[A_D_E_P_T]

Situation normal.

Consider the discovery of valproic acid:

"Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder."

To this day, nobody knows exactly how it works, apart from the fact that it hits more than a few targets. (And it's a particularly potent inhibitor of the epigenetic modulator histone deacetylase.)

Apart from a subset of very clear-cut cases -- steroid hormones, peptide hormones, and certain aggressive chemotherapeutic drugs -- there's no clear model for most small molecule drugs. Even really mundane ones like metformin and paracetemol are very imperfectly understood.

[Ezku]

Your point is a very important one. Do we check the interactions of a tentative drug molecule against every single molecular target in the body, and do we track what happens as a result of all those interactions? It’s quite common that a group of ”usual suspects” on the researchers’ radar get checked for — but by necessity, a lot of ground goes uninvestigated.

  > Consider valproic acid: For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds

Speaking of ”inert” solvents:

  > Dimethyl sulfoxide (DMSO) is the most common organic solvent used in biochemical and cellular assays during drug discovery programs.
  > Despite its wide use, the effect of DMSO on several enzyme classes, which are crucial targets of the new therapeutic agents, are still unexplored.
  > 1-4% (v/v) DMSO, the commonly used experimental concentrations, showed ∼37-80% inhibition of human acetylcholine-degrading enzyme, acetylcholinesterase (AChE)

(DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase. ACS Chem Neurosci. 2017 https://pubmed.ncbi.nlm.nih.gov/29017007/)

Oops! How many investigations on specific drugs were in fact showing mostly the results of what happens when interfering with one of the most ubiquitous-yet-underappreciated signalling systems, the cholinergic system?

I’m hoping widespread & systematic application of modern methods like in-silico molecular docking studies will lead to much fewer such oversights.

[_Wintermute]

That's what controls are for, you're always comparing against the DMSO control. I also don't think anyone who's doing small molecule screens thinks DMSO is inert.

[aatd86]

Normal might be a strong word. It messes with the brain which is the core.

Goes to show a lot of clinical medecine is about short-term relief and not necessarily about real health.

If you really look at it with unbiased eyes, between elective surgeries and what not, it's not really about curing any true dysfunction sometimes. Perhaps too many times.

We just go with the flow but, heck, MDs are not even necessarily healthier than you, some even smoke to this day!

Go figure...

[crooked-v]

You've gone off on an unrelated tangent here. "Situation normal" in this case means that, as with lots of drugs, we only poorly understand the mechanism by which they actually work, and that new discoveries can completely change our understanding of how to use and improve on them.

[aatd86]

Well I don't think that this is a tangent at all then.

What I said is still exactly on point.