Bob the Grumpy Med Chemist

Jaded. Let me know when one of you figures out how the human body works.

[Bob the Grumpy Med Chemist @med_chemist]

@raffcolo @ducholab @KRHornberger Indeed!

I've always thought that this must really irk professors who spend a lot of time teaching 1st year chemistry undergrads significant figures, and then turn around to read the literature full of grad students and PhDs constantly butchering the rules

[Bob the Grumpy Med Chemist @med_chemist]

@BagPhos I'll take his scorecard though!

[Bob the Grumpy Med Chemist @med_chemist]

@BagPhos Could you please clarify how I obtain the solvent named "obvious to those skilled in the art" :)

[Bob the Grumpy Med Chemist @med_chemist]

@KRHornberger has several useful past posts on the relevant kinetics here, if helpful.

[Bob the Grumpy Med Chemist @med_chemist]

Have seen this a couple of times recently:

If you are reporting the results of a kinase panel in a paper, please make sure to include not only the concentration of compound used, but also the concentrations of ATP used in said panel.

[Bob the Grumpy Med Chemist @med_chemist]

I've previously collected similar articles with useful warnings and tips about methods such as scavenger reagents.

See them by following the linked threaded tweets

https://t.co/jBqYDJpUKG

[Bob the Grumpy Med Chemist @med_chemist]

Glad there is room for papers like this to be published. https://t.co/DJnZgeAydG

I hope there will be some follow up on the original ACS Med. Chem. Lett. paper on the supposed probe.

Some other references on metal impurities linked below, if useful.

[Bob the Grumpy Med Chemist @med_chemist]

Wonderful little paper here with many useful warnings inside:
https://t.co/xvIFI0eDEi
Practical notes:
-Do fresh resynthesis (orthogonal route a +)
-Test potentially interfering salts+compounds in assay
-Lots of things bind and give Xray structures at mM

More warnings below...

[Bob the Grumpy Med Chemist @med_chemist]

@MoleculesGoHard Just needed to get out and see the world for a bit :)

[Bob the Grumpy Med Chemist @med_chemist]

I'm extremely pleased people are working on novel antibiotics.

But it still makes me a bit sad that this is the PK characterization of the key compound in the world's purported premier science journal:

[Eric Topol @EricTopol]

What if there was an antibiotic that doesn't disrupt the gut microbiome?
There is now.
A discovery published @Nature today
https://t.co/njtUddaJHo @PaulHergie and colleagues @UofIllinois @justsaysinmice

[Bob the Grumpy Med Chemist @med_chemist]

@AdamQuic Happy to. @KRHornberger has provided some great resources around PK reporting, such as the thread below https://t.co/DzrareLoFO

Regarding the nature paper, the issues are unfortunately beyond lack of data, and show a misunderstanding of the usual meaning of the parameters.

[Keith Hornberger @KRHornberger]

🧵PSA: we need to chat about pharmacokinetics & pubs. If you plan to publish in vivo PD/efficacy studies, the minimum credible accompanying PK package is an IV leg + an IP/PO leg if that's your eventual route. In the same species, preferably at the planned efficacy dose. 1/

[Bob the Grumpy Med Chemist @med_chemist]

@BagPhos @KRHornberger Missed the chaos of this twitter thing a bit too

[Bob the Grumpy Med Chemist @med_chemist]

@jsrosenblum Guilty!

[Bob the Grumpy Med Chemist @med_chemist]

@BagPhos @KRHornberger :)

[Bob the Grumpy Med Chemist @med_chemist]

@KRHornberger Clearly you need to keep spreading the good word on proper PK reporting :)

[Bob the Grumpy Med Chemist @med_chemist]

@thederzzz @KRHornberger Regarding the paper with the odd PK table in my original post, some of the parameters mentioned do not match their usual definitions.

[Bob the Grumpy Med Chemist @med_chemist]

@thederzzz Sure! @KRHornberger has been fighting the good fight on here about proper PK reporting.

This and other resources of his should be a good starting point:
https://t.co/DzrareLoFO

[Keith Hornberger @KRHornberger]

🧵PSA: we need to chat about pharmacokinetics & pubs. If you plan to publish in vivo PD/efficacy studies, the minimum credible accompanying PK package is an IV leg + an IP/PO leg if that's your eventual route. In the same species, preferably at the planned efficacy dose. 1/

[Bob the Grumpy Med Chemist @med_chemist]

On the other hand, the efficacy data for antibiotics does mitigate the risk of mischaracterization a bit. Paws up / paws down is a pretty clear endpoint!

https://t.co/oMpjUCMgmJ

[Bob the Grumpy Med Chemist @med_chemist]

I propose a solution to 2 problems:
- Lack of novel antibiotics
- Abundance of terrible in vivo efficacy studies

Solution:
If you publish a bad efficacy study, you must instead work on antibiotics development, where output of animal model is much clearer... paws up / paws down

[Bob the Grumpy Med Chemist @med_chemist]

@VRBoombatzMDPhD @KRHornberger @D_B_McConnell @agwaterson Right, fair point that it’s definitely a simplification, but at least clarifies that you can’t win the game simply by moving the PK curve higher and higher, and brings the idea of a therapeutic window into focus.

[Bob the Grumpy Med Chemist @med_chemist]

After good data: "May I die if I were to change places with the Persian king!"

After bad data: "You know, maybe leaving behind chemistry in exchange for my own kingdom would be a sensible choice if given the option."