- Arteminisin-based therapies are the absolute mainstay of malaria treatment the world over, so this new paper deserves attention. The drug is often given in combination with the older aminoquinoline agents like choloroquine, piperaquine, and amodiaquine, but the authors here make a strong case that this is actually counterproductive. As the paper notes, heme is central to the mechanism of action for both kinds of drugs. The aminoquinolines bind to it and affect heme homeostasis, and may well product toxic adducts […]
- I spent a day at Williams College last week, which I enjoyed very much, and I found a part of my lecture there overlapping with a big topic in undergraduate education. I have a section in several of my talks where I speak about AlphaFold-type machine learning and its implications for drug discovery, and that seemed to fit rather closely into concerns that many professors are having about the effect of AI systems on coursework and learning. I’m sure that […]
- I often get asked what areas of drug discovery look most likely to bear AI-driven advances into the clinic, and my usual answer is “therapeutic antibodies”. Thats because it’s a protein-centric problem in the actual modeling, and we know quite a bit already about antibody structures (at least as compared to the much large wild-type protein structural landscape). And that’s because antibodies themselves are a (relatively!) constrained space within that larger one, although don’t let anyone tell you that it’s […]
- If you look at cells dispassionately, one of the things that strikes is that man, do we ever have a lot of ribosomes. These are of course the protein-synthesis machines that are kept humming nonstop as RNA sequences are translated into protein sequences, and ribosomes themselves are structurally a mixture of proteins and some unusual RNA molecules all their own. The peptidyltransferase center (PTC) where the actual synthesis of new peptide bonds takes place is itself a flat-out ribozyme, an […]
- Longtime readers will recall the fuss I made about the “synthesis machine” work from the Burke group at Illinois. That involved iterative coupling of boronic esters with MIDA boronates, which were then deprotected to plain boronic esters, which could then be coupled with a further MIDA boronate, and you get the idea. It’s a scheme for directed carbon-carbon bond formation, and when you get down to it, a lot of organic synthesis is in fact a scheme for directed carbon-carbon […]
- So let’s finally talk about peptides. And I don’t mean peptides as chemists and biologists understand them (short chains of amino acids) I mean “Peptides!”, the hot new wonder drugs that you can order by mail. Oh man. The first barrier to writing about this situation, for someone like me, is that difference in terms. For a chemist, “peptide” has a pretty clear definition: any relatively short chain of amino acids, and when they get longer we go ahead and […]
- Here’s an interesting surprise: an opiod agonist with what seems to be fewer side effects. That’s been a tricky thing to manage – all the morphine-type compounds have the well-known liabilities (addictive potential, respiratory depression, gut motility and more), and the synthetic ligands like fentanyl certainly don’t avoid these either. In recent years there’s been a revival of interest in an older class of molecules called nitazenes, but unfortunately a big part of that interest has come from drug cartels: […]
- By this point a lot of companies have made a lot of PROTAC bifunctionals. Those, as my readers in the business well know, are large species that have two “business ends” tied together by some sort of linking group. One end binds to a protein of interest (POI) and the other to a protein that is involved in the protein degradation machinery (typically an E3 ligase enzyme). Having these in the same molecule lets you bind to your target and […]
- In today’s “Well, I’ll be darned” category is this paper, which described a way to get drug delivery into the brain that I never would have imagined. The authors are using a “calvarial” mechanism, and I’m certainly in a forgiving mood if you’ve never heard that word before, because I certainly hadn’t. The calvaria, as it turns out, is the top of the skull, and the skull bones have a lot of anatomical detail in them. The inner and outer […]
- Now here’s something that I wouldn’t have guessed. As the world knows, lipid nanoparticles have been the key to getting mRNA vaccines to work, and they are useful for all other attempts to deliver RNA cargoes into cells and probably much besides. A huge amount of effort, time, and money has been put into trying to optimize them for these purposes – all sorts of different lipids and lipid mixes, close attention to size, morphology, and cargo loading, you name […]
- The development of chimeric antigen receptor T-cell (CAR-T) therapy continues, and some really interesting new directions are being explored. As it stands, this treatment can be extraordinarily effective in some patients, and these are generally people who have been through every other option for their cancer therapy. But there are some real limitations, even for treating patients with the leukemia/myeloma type cancers that (so far) this mode is best suited for. An obvious one is the sheer amount of time […]
- Here’s a look at one of the most famous opioid agonists in the world, fentanyl. You might think that by this point we would have a pretty thorough understanding of the drug’s behavior and the factors that lead to its (notorious) potency, but such GPCR ligands it seems that there’s always more to discover. The authors here are working off recent results from patch-clamp receptor assays in whole cells that suggested that fentanyl (but not the classic opioid ligand morphine) […]
- Time to think like a biochemist! And that means paying close attention to energy transactions in a cell, because the science of thermodynamics makes it very, very clear there there is always a bill that has to be paid. Most of the time, the currency involved is of course ATP, since breaking that down to ADP gives you an immediate payout. ATP hydrolysis and the other sources of chemical energy (like acetyl-CoA) function as “battery packs” for all sorts of […]
- Here’s a paper evaluating a popular AI/ML model for cofolding ligands and proteins, Boltz-2. This is of course a problem of extreme interest to the drug discovery community, as well as to all sorts of people working on cell biology, structural biology, and related fields. It’s been one of the goals for decades to start from scratch with a protein sequence and a small molecule and be able to say “Does this molecule bind to this protein? How well?” And […]
- Here’s the other cognition/aging/Alzheimer’s paper that caught my eye. In a similar way to the work I highlighted yesterday on proteins released by the liver affecting the blood-brain barrier and overall brain function, this one is finding another external signal, from from an unexpected direction. The authors studied the intestinal microbiomes of mice as they aged, and found that species that produce medium-chain fatty acids become more and more prevalent. Then a complex series of events start taking place: these […]
- I’d like to highlight a couple of interesting papers with a bearing on Alzheimer’s and aging in general – well, I hope that they will turn out to have one, because right up front I have to note that they’re both in rodent models. But the unusual mechanisms in both cases are the sort of thing that could translate to humans, and could also be fairly readily checked. We’ll do one today and another tomorrow. This paper is building on […]
- I really got a kick out of this recent paper, but that’s probably because I’ve always enjoyed the whole “templated ligation” or “kinetic target-guided synthesis” field. There are several ways to describe it in the literature, which doesn’t make searching for papers any easier, but the basic idea is that you get two partner species to react in the presence of a binding site or surface. If you pick your chemistry right, that reaction/ligation/bond formation/condensation is something that normally has […]
- Let’s start off the week with some good news. There was a small company called Anacor that specialized in boron-containing drug leads, especially for infectious diseases. They had some shots at the clinic in that area and had an antifungal (tavaborole) approved by the FDA, but their biggest success was a topical medication for dermatitis called crisaborole. That’s a PDE4 inhibitor, although it has to be said that the exact mechanism for its efficacy in this disease is (to my […]
- We find ourselves in a situation where chemistry is intruding on current events, and I’m referring to something that not everyone seems to have thought about: fertilizer, and especially nitrogen fertilizer. What it is, how it’s used, and especially where it comes from. Intro to Fertilizer Now that's a grabber of a subhead, right? But if you’ve bought a bag of the stuff for your garden or your houseplants, you’ve seen the three numbers used to show the strength and […]
- I enjoyed this paper, because it plays to my own prejudices. I’ve long believed that assays and experiments should be conducted as close to the real biological systems as is feasible, and that if you are (perforce) starting in more simplified ones, that you should move up the scale as soon as you can. That means if you show up with purified protein assay data, I’ll ask when it’s going into cells, and if you have cell data I’ll ask […]
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