- 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 […]
- I recommend anyone who wants to learn more about generic drug manufacturing to read this article at the New York Times (it’s a gift link, free to read). There’s been a lot of coverage of drug manufacturers “on-shoring” production and packaging in response to pressure from the Trump administration, and there is definitely some of that happening (although it doesn’t happen as quickly as it might seem to). But this is another world entirely. That’s because the generic drug business […]
- I have lost count of the number of times over the years that I’ve said “Huh, I didn’t think mass spec could do that”. So you’d think that I would be used to this by now, but apparently not, because that was my exact reaction to this new paper. It’s from a team of groups at Leiden, Utrecht, and Jena, and they report a “self-encoded library” technique for some pretty large-scale screening. It should be noted up front that there […]
- It is a longstanding dream of mine that some day, some year I will no longer feel obliged to write disparaging blog posts about Sarepta and their Duchenne muscular dystrophy drug portfolio. I have been doing that for a loooooong time now (twelve years?) as the company, with what from one perspective is admirable persistence, has continued to develop and test various small-molecule drugs and gene therapies. My misgivings have come from the clinical trials of these agents, which have […]
- I’d like to take a bit of time to note this paper and its authors. It was published in May of this year in JACS, and it was about the conversion of carbon dioxide to methane. That’s certainly of great interest – it’s basically “reverse combustion”, and as you can imagine there are a lot of people interested in taking industrial carbon dioxide emissions and sending them back around by such a process. You could even imagine a technology that […]
- The “nocebo” effect is something that makes a lot of sense when you think about it, but it still seems weird. Everyone has heard of the placebo effect, where some interventions tend to have a beneficial effect if you think that they’re having (or going to have) a beneficial effect. There is no doubt that this is real, although its magnitude varies a great deal depending on circumstances, as it well should. The nocebo effect is just that with the […]
- Here’s another example of an idea that has been kicking around for years in medicinal chemistry without ever really breaking through: substituting a silicon atom for a carbon. To be fair, most of the time this doesn’t seem to do all that much, while introducing various uncertainties around ADME and toxicity (since we don’t have all that much experience with organosilanes as drugs). So you can see why we’re not overrun with “silyl switch” compounds. But at the same time, […]
- I think that I can guarantee that you haven’t heard this phrase before: “ballistic microscopy”, the subject of this recent preprint. What the authors describe a combination of near-medieval technology on the one hand and cutting-edge analytical work on the other. They are bombarding cells with focused streams of gold nanoparticles (which range from 50 to 1000 nm diameter). These things are traveling at speeds up to 1 km/sec (over 2000 miles per hour (edit: fixed!)) and blast straight through […]
- This is a rather unexpected article that suggests that some mRNA vaccines can potentiate the actions of some immune-checkpoint therapies used in oncology. Specifically, the authors find that the mRNA coronavirus vaccines significantly increased overall survival rates in those patients who were getting anti-PD-1 antibodies as immune checkpoint inhibitor therapy (!) In a welcome reverse of the usual way we end up studying cancer therapies, this effect could be replicated in mice. There was a strong synergistic effect of mRNA […]
- Ah, quantum mechanics. We’ve known about it for a hundred years now, and it’s still as weird as it ever was. This paper has a case in point: the authors are investigated a catalytic hydrogenation reaction, the reduction of a benzyldehyde to a benzyl alcohol with hydrogen gas and a palladium catalyst dispersed on a titanium particle surface. There are a lot of ways to get this sort of reaction accomplished, and they occur through a lot of different mechanisms. […]
- Now, transcription and translation are indeed wonders of nature. The constant reading-off of our genetic code and its expression into proteins kind of has to be at that level, you’d figure, for living cells to work at all. But it’s important to remember that not-so-exact versions of these things are important, too. I’ve written about how error-prone mechanisms can be useful for bacteria and viruses (and indeed, how switching gears to these can be an outright roll-the-dice survival mechanism). But […]
- As I have stated several times over the years here, intrinsically disordered proteins make me uncomfortable. I mean intellectually; biochemically they are keeping me (and the rest of us) alive, because they are crucial to cellular function in a number of ways. My mental difficulties are because of my background as a small-molecule organic chemist, because small molecules – okay, most small molecules – have defined structures and shapes. That leads right to a mental model of enzyme function where […]
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