@med_chemist

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

 Armchair
Joined May 2021
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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.
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@KRHornberger has several useful past posts on the relevant kinetics here, if helpful.
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Wonderful little paper here with many useful warnings inside: pubs.acs.org/doi/10.1021/acs… 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...

Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays

Abstract. Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS “on” remains of great importance to clini

pubs.acs.org
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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 xitter.cf/med_chemist/status/151…
Bob the Grumpy Med Chemist@med_chemist23 Apr 2022
Glad there is room for papers like this to be published. pubs.acs.org/doi/10.1021/acs… 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.

Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating...

Abstract. Ten eleven translocation (TET) dioxygenases 1–3 are non-heme Fe­(II) and α-ketoglutarate dependent enzymes that catalyze oxidation of 5-methylcyt

pubs.acs.org
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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
@EricTopol29 May 2024
What if there was an antibiotic that doesn't disrupt the gut microbiome? There is now. A discovery published @Nature today nature.com/articles/s41586-0… @PaulHergie and colleagues @UofIllinois @justsaysinmice
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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! xitter.cf/med_chemist/status/154…
Bob the Grumpy Med Chemist@med_chemist28 Jun 2022
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
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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."
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Having just read the article, this was quite apparent:
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If I were the patient, I’d be a bit concerned that the “Amount” field of the label is basically unintelligible
David Juurlink@DavidJuurlink4 Feb 2023
Me: “So, how’s your pain this morning?” Patient, pointing to IV: “This stuff is amazing.” The stuff:
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Forgot to provide the answer: US20220402883 - COMPOUNDS AND METHODS FOR MODULATING RNA FUNCTION
Bob the Grumpy Med Chemist@med_chemist18 Jan 2023
@dragon38073853: we miss you posting fun patent structures... Can you all guess the target of these compounds?
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Just a reminder to any of you mixing drinks tonight: grapefruit juice is good for masking the taste of alcohol, but beware of juice-drug interactions!
Bob the Grumpy Med Chemist@med_chemist31 Dec 2021
Bob's Med Chem Fact of the Day: In the 80s, like many of you tonight, scientists were searching for the best juice to mask the taste of ethanol. They chose grapefruit juice. The eventual study would lead to the surprising discovery of strong grapefruit juice-drug interactions.
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Estimated total $$$ spent making compounds based on misanalyzed SAR — chasing noise rather than true signal… A Fermi estimate to absolutely no significant figures: WAY TOO MUCH
Keith Hornberger@KRHornberger28 Nov 2022
Sunday night rant: med chemists and friends, please, in the name of all that is holy, pay attention to significant figures. If I see one more IC50 reported as 10.407 +/- 1.708 uM, I’m going to lose my mind. Y’all learned this in high school ffs. Just stop it.
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Good thread and responses. And before initiating a study always ask: "how will the med chem/discovery strategy change based on the results of this?" Amazing how often people want to spend time+$$$ on studies that will not change anything besides satisfying intellectual curiosity
Keith Hornberger@KRHornberger20 Nov 2022
Drug Discovery Axiom 6: take measured risks; spend the money, save the time. Folks are often miserly with assays & skimp on study designs. It’s a mistake. All of this pales in comparison to the cost of lost time moving a drug to the clinic & market. Value time correctly.
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The Nobel Prize in Chemistry is awarded for the naming of "fancy-name." Though no practical use cases have yet been discovered, the creation of "fancy-name" has led to hundreds of papers and reviews noting the promising potential applications of "fancy-name."
Keith Hornberger@KRHornberger4 Oct 2022
The chemistry Nobel will be announced tomorrow, so it’s that time again! Who will win this year? Wrong answers only.
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I pose the following solution: - Make med chem (somewhat relevant to physicians) a required course for pre-medical students - Make organic a prerequisite for med chem - Organic chem courses are now highly relevant Now all the students get to be even more angry at chemistry!
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Now quite annoyed I didn't get at least 10 J. Med. Chem. papers from the last time I was working on a diastereomeric series: doi.org/10.1021/acs.jmedchem…

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV‑2 Main Protease

Abstract. SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (Mpro, 3CLpro) of SARS-CoV-2 is a key enzyme that processes pol

pubs.acs.org
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5 easy steps to become a modern grumpy med chemist: - Have a HTS return no useful hits - Have a virtual screen return no useful hits - Have a fragment screen return no useful hits - Have a DEL screen return no useful hits - Have a literature compound fail to reproduce
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Perhaps a certain journal and its editors could lead the way in changing this culture, to a world where particularly useful negative results are seen as essential to the main body of the paper. Hint. Hint. Wink. Wink.
J Org Chem/Org Lett@JOC_OL8 Sep 2022
Replying to @JOC_OL
As an author, it is hard to put lots of negative examples into a paper because of fear reviewers will not be positive. But what about putting tables of unsuccessful substrates in the SI? #OLAskTheEditor
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Fun, COVID related fact: When Kariko and Weissman first went to publish their paper showing the uridine -> pseudouridine switch suppressed the immunogenicity of mRNA. It was instantly rejected by Nature, Science, and Cell as "Incremental" Kariko even had to look up the word!
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Sources: doi.org/10.1016/j.cell.2021.… doi.org/10.1073/pnas.2119757… Their 2005 paper in Immunity is doi.org/10.1016/j.immuni.200…
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Also this is why all you spring chickens should take up the habit of reading accounts of old, obscure papers :)
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