- I’ve kicked around the idea of doing some “Where Are They Now” posts here, and I think that this is as good an occasion as any. Back in 2018, I wrote about a new company called Verge Genomics that was using AI/ML methods to go after neuroscience targets like ALS, and my eye was caught by statements like “Instead of tediously screening millions of drugs, the algorithm will computationally predict drugs that work” and “We've discovered a way to map […]
- Here’s a neat look at microbial natural products from a chemical diversity standpoint. Of course, natural products have a fearsome (and well-earned) reputation for displaying structures that we humans would never have gotten around to making – or even thinking of – but once you get that internalized, there are some interesting patterns and lessons. The author (Roger Linington at Simon Fraser Univ.) is also looking at two trends that at first seem to be at odds with each other: […]
- We have been making small-molecule inhibitors of kinase enzymes for quite a while now in medicinal chemistry, and I would not even want to guess how many such compounds have been described in the literature. As an aside, this is usually the point where someone who’s been around as long as I have recalls that there was a time when people thought – not without some reason – that making such selective kinase inhibitors might not be possible at all. […]
- It’s been obvious for many years now that growing antibiotic resistance is a problem, and that it could turn into a very bad one. There has been a great deal of work put into trying to understand the nature of these resistance pathways, but if you’re studying bacterial pathogens in the modern world, you’re showing up at the crime scene long after the break-in. You might be surprised to learn (I was!) that there is actually a resource of pathogenic […]
- I found this to be an interesting paper, and it uses an idea that’s not always easy to realize. There are a lot of time when we’d like to be able to use small proteins and peptides as drugs, but they often have poor pharmacokinetics (absorption, membrane penetration, and most especially metabolic liability). In addition, some of these small-protein ideas can end up being immunogenic, since your body can react to them like the foreign substances they are, with your […]
- I enjoyed reading this new synthetic paper, because I can still remember when I learned about the good ol’ Sandmeyer reaction in sophomore organic chemistry class and these authors are among the many people trying to replace it. There’s a reason for that, because while the Sandmeyer is definitely old, it ain’t always good. It’s a reaction that lets you take an aromatic amine (of which there are a great many) and convert that amino group into a wide variety […]
- The whole “Are there weird electric fields at the surface of water droplets” question is not getting any easier to understand. I last wrote about this topic here). There are several subsidiary questions that go off in different directions: does unusual chemistry actually happen at air-water interfaces (and is this more prominent, as you might expect if true, in small droplets that are mostly surface area?) Or are these reports (mostly) experimental artifacts? If it does happen, what’s the mechanism? […]
- Some chemistry today, drawn from real life (mine, anyway). I was setting up a short series of palladium-catalyzed couplings the other day (Buchwald-Hartwig type, C-N bond formation), and since there were very close precedents to my structures in the chemical literature, I naturally just borrowed the known conditions. There was nothing out of the ordinary about them; it seemed as if they’d work about as well on my starting aryl bromides as it did on the ones already described. (Edit: […]
- Well, here’s another report of a GLP-1 agent being tried in Alzheimer’s patients (after this recent post was written). The last one didn’t show much, so let’s have a look. In this trial, 204 patients with mild-to-moderate Alzheimer’s were treated with liraglutide (daily injection) versus placebo for one year. The doses started at 0.6mg and worked up to 1.8mg, which is the typical starting dose for diabetes therapy working up to the maximum approved one. The primary outcome was looking […]
- It is next to impossible to keep up with all the chaos in the Trump administration’s staffing of the public health agencies (NIH, FDA, and all the ones under them). I haven’t tried to cover it all blow-by-blow, because it would exhaust me and exhaust you the readers, and to what end? You can make out the main points of the Trump/RFK Jr. approach pretty easily. One of those is clearly, obviously, a multipronged attack on the practice of vaccination. […]
- This is a good look at the current state of the art in creating peptidic binding ligands to protein targets out of thin air – well, “one-shot computation” is probably the more preferred term, but you get the idea. One expects this to start to be more feasible with such peptide ligands because of several factors: the modular nature of the peptides, for starters, combined with a limited number of amino acid building blocks both make the problem more bounded […]
- There have been some interesting failures recently in Alzheimer’s trials. As long-time readers will know, I consider basically all Alzheimer’s drug trials to have failed to one degree or another, and particularly when it comes to clearing the “will improve patient’s lives in the real world without putting them at too much risk” hurdle. But these two are notable because they’re aimed outside the usual amyloid zone. First off, Novo Nordisk reported that semaglutide (the company’s GLP-1 agonist drug, of […]
- This paper advances a metabolic hypothesis that I certainly didn’t see coming. One of the great mysteries about alcoholism/alcohol use disorder is its underlying biochemical drivers. There’s obviously a behavioral and psychological component, but there are physical and metabolic ones too, and trying to untangle those has been an effort of many decades. The authors here note a long-running series of observations about alcohol and sugar consumption. For one thing, laboratory rats that are given access to alcohol will in […]
- Here’s a phenomenon – yet another one – that never crossed my mind before. It’s long been known that enzymes that catalyze proteolysis (cleavage of peptide bonds) can, under certain circumstances, catalyze the reverse reaction of peptide bond formation. Folks who have had to think about chemical kinetics will immediately realize that those conditions would include high concentrations of the two cleavage products and low concentrations of the longer protein substrate, an example of Le Chatlier’s principle in action. It’s […]
- This is a very useful article on phenotypic screening, and is well worth a read. And if you haven’t done this sort of screen before but are looking to try it out, I’d say it’s essential. The authors (both with extensive industrial experience) go into detail on the factors that can make for successful screens, and the ones that can send you off into the weeds. There are quite a few of the latter! For small molecule screens, you need […]
- As regular readers well know, I get very frustrated when people use the verb “to reason” in describing the behavior of large language models (LLMs). Sometimes that’s just verbal shorthand, but both in print and in person I keep running into examples of people who really, truly, believe that these things are going through a reasoning process. They are not. None of them. (Edit: for a deep dive into this topic, see this recent paper). To bring this into the […]
- I wanted to mention a couple of recent papers about a field that’s had a lot of interest over the last decade: engineered two-dimensional materials. These things are (at their theoretical best) only one layer of atoms or molecules thick, and can have a great many exotic and useful properties. Some of those are still a bit more theoretical than actual, but they range from optical and electronic behavior all the way to sheer physical processes like molecule-scale filtration. For […]
- Here’s another example of biochemistry being weird, one that I had never come across until recently. Did you know that there are enzymes that are dependent on tungsten (of all things?) As far as we know, they aren’t found in higher organisms, but they are scattered across a number of bacteria and archaea. There’s a whole related family of molybdenum-dependent enzymes that I had heard about, but there is indeed a group that can only use tungsten. Both of these […]
- Some weeks back I wrote about a paper suggesting that for many organic chemistry reactions stirring is not very necessary. That one sure set off a lot of comments (here on the blog, on social media, in my own email and conversations, etc.)! I wanted to revisit the topic in light of two more publications since then. First off is this preprint, a swift response to the original, from a group of industrial chemists. They do a good job of […]
- A few years ago here, I wrote about an interesting hypothesis involving the TrkB receptor and the action of antidepressant drugs. The short form of that one is that TrkB is important in the signaling and action of the BDNF neuronal growth factor, and BDNF in turn has been the subject of several theories about major depression. The claim was that the BDNF/TrkB complex produces a small molecule binding site that accommodates many known antidepressant molecules, a use for them […]
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