Cow tips and other drug discovery facts

Bob discovers that he is the only person still around in August

Last Week’s Facts:

All the facts from August so far can be found here

In review: August 2021 Facts of the Day

As the title of this post indicates, one of these facts indeed involved cattle

Bob the Grumpy Med Chemist @med_chemist

Bob's Med Chem Fact of the Day: "Fog fever" or "Cow Asthma" occurs when you move cattle too quickly from indoor feedlots to lush, protein rich pastures. The reason for this connects back to a classic "structural alert" in med chem. ->

Bob the Grumpy Med Chemist @med_chemist

Essentially, the rumen of the cattle cannot adjust quickly enough to the protein rich grass with lots of tryptophan. Bacteria in the rumen convert tryptophan-> indoleacetic acid->skatole (3-methylindole). Skatole goes into circulation and goes to club cells in bronchioles. ->

Bob the Grumpy Med Chemist @med_chemist

There are a lot of CYPs in these cells that convert skatole to the reactive metabolite, 3-methyleneindolenine. This reactive intermediate is then toxic to the cells in the lung. Emphysema, pulmonary edema, and often death are a result. ->

Bob the Grumpy Med Chemist @med_chemist

This is why 3-alkylindoles, which can form similar reactive metabolites, are often a structural alerts in medicinal chemistry. sciencedirect.com/science/articl… gives the examples below of where the reactive metabolite formation is observed

The post linked above includes many other facts from the past week that are hopefully educational. I’ll give special mention to a paper I mention which provides a great overview of all of the pain one can experience when validating HTS hits.

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Let’s Go to the Polls

Last week, I ran my first Twitter poll. Here were the results:

As one commenter @jsrosenblum mentioned, it would be useful to know the base rate to the simpler question, “would you ever enroll in any clinical trial?”

Overall, I’m not quite sure what to make of the poll. Clearly a lot of chemists believe their view of a structure is in some way predictive of potential side effects or other attributes of the molecule. Of course, we have to square this percentage with the fact that we are typically terrible at predicting many toxicities/side effects in the clinic. However, if I were told that I was in a trial for a molecule with a novel covalent warhead, I might let the trials to go ahead without me too, depending on level of sickness. Clearly context matters.

One final consequence is that most of us feel the average patient does not have all of the necessary information to make the most-informed decision possible about trial participation. That point is a bit more worrying.

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A few classic first lines:

The other day, I had fun with classic first lines of novels and adapted them for drug discovery papers.

Bob the Grumpy Med Chemist @med_chemist

Good first lines for drug discovery papers: "This project was dead to begin with." "It is a truth universally acknowledged that a single asset biotech in possession of venture capital funding must be in want of a clinical candidate"

and many more in the thread if you click on the tweet.

If you know of any other good first lines of novels that translate well to drug discovery, do let me know in the comments! I certainly haven’t caught them all.

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Some other facts from the farm:

Continuing the theme from the cattle fact above, one agricultural fact I did not know was about exploding pistachios. Thanks to @Chemjobber on Twitter for sharing that article.

This also reminds me storing hay indoors on a farm. It’s actually the high moisture content hay you have to watch for combustion. Seems pretty counter-intuitive at first glance doesn’t it?

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Some cartoons to bring you joy while automatic out of office emails bounce back to your inbox:

Bob the Grumpy Med Chemist @med_chemist

Well done @NewYorker

Bob the Grumpy Med Chemist @med_chemist

This is sometimes what I feel like is happening after I get chemistry quotes for synthesis