Remdesivir is an analog of adenosine, one of the four building blocks of RNA. Just look at the main structure and you'll agree they look similar. It turns out the mechanism of action of this drug is that it's supposed to be confused with adenosine, so that the viral RNA replication process uses remdesivir instead of adenosine, which later breaks the RNA†.
Our body, or really, all biological processes can synthesize incredibly complicated molecules that can take human chemists a huge amount of effort to synthesize. It really is amazing how awesome our body is.
†: My description here is a dumbed down description. For a more precise description see section 2 of Arguments in favour of remdesivir for treating SARS-CoV-2 infections, Wen-Chien Ko et al, https://www.sciencedirect.com/science/article/pii/S092485792...
> The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus.
Absolute gibberish to someone with limited knowledge of biology.
There has been exciting work on directed evolution of enzymes for drug synthesis, particularly for transamination (conversion of a ketone to an amine). This is I believe being used commercially now, for example for the production of the diabetes drug sitagliptin.
This mode of action is fascinating, some HIV medications work in a similar way.
What I’m curious about is why this huge group attached to the adenosine-like group is needed. It seems to be rather complex for being a shoe to be thrown into cellular gear.
Do you have an idea or pointer into the mode of action of this group?
Out of curiosity: We seem to have a very good understanding how synthesis in biological processes works (from DNA to the eventual molecules), we are able to create DNA/RNA molecules with arbitrary content and we're increasingly able to simulate what molecule a particular nucleotide sequence would produce.
So, putting the three together, would it be possible to use actual biosynthesis for designed molecules by basically writing your own DNA/RNA and inserting it into a cell?
This article really reinforces my choice to drop ochem in college. It's funny how deciphering assembly code seems downright mundane compared to this jargon. Like, I get how given the process you could recreate things, or you could devise possible reactions based on electron shells and bonding tendencies, but how do researchers even figure out how to make these reactions happen? Especially when they require -100C, or +5atm of pressure.
> but how do researchers even figure out how to make these reactions happen?
Disclaimer: I'm terrible at organic chemistry.
As with software engineering, you develop a general sense (I didn't) of what might work and what probably won't. You aren't coming at it blind and reinventing the wheel every time. You learn to recognize patterns in chemical structures and reason about how they will interact under various conditions based on that. You do electron pushing in your head without giving it much thought, similar to a programmer reasoning about object lifetimes or dataflow in an application.
As to -100 C or +5 atm, that's the easy part. You alter environmental conditions when what you're working with is too reactive, or not reactive enough, or you have some other general problem. It's roughly analogous to determining the minimum amount of RAM the machine hosting your production database requires.
> but how do researchers even figure out how to make these reactions happen? Especially when they require -100C, or +5atm of pressure.
That part, at least in theory, is easy to understand.
Chemical reactions are typically of the form:
ingredients + energy -> products + byproducts
If the energy is on the left-hand side, making the environment warm makes the reaction go faster. If energy comes out (so it's on the right-hand side), making it cooler is better. You also need to control the temperature to be in a range where both the ingredients and products can survive.
As for the pressure, if the products and by-products have more total volume than the ingredients, low pressure is good. If it's the other way round, high pressure encourages the reaction.
The more complicated part is that if multiple reactions can happen with the same ingredients, or if the products can do further, unwanted reactions. Then you have to balance out the parameters to encourage just the reaction you want, and to discourage all the others.
Not a biologist or chemist, but the articles I've read that invoke biochemistry or molecular biology always reminded me of the intricate mechanical automata that were constructed before electricity could be used for computation.
Back then, you had a certain number of mechanical properties in mind as well as well-known "parts" (gears, linkages, etc) that you could predict the properties of very well - and the task was then to assemble them into larger mechanisms that did what you wanted them to do.
Seems to me, the intuition here could be similar - except the number of dimensions in which parts can interact is larger, the "clockworks" are orders of magnitude more complex - and your tools are much more coarse, so mostly, even if you know what you need to build, the building itself can only be done indirectly.
Organic chemistry is basically doing constraint solving. E.g. you know a lot of different reactions (e.g. replace Cl by OH, add double bond), but some reactions cannot be done depending on the structure of the intermediates.
I have a bachelor in chemistry and ochem was one of the most painful classes based on the amount of things you must know by heart for synthesis
Really interesting getting a window into the world of professional chemistry. So impactful on all of us but so much more opaque. We see CS jokes/memes all over the place, even if only those who program get them, but we never see chem jokes, or only sparingly and rarely beyond a high school level.
I wish I knew the havkernews equivalent for chemistry, finance, etc. The closest thing I've found was https://www.foundmyfitness.com/news for nutrition.
In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail.
1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but reality was far different. You don’t think much about side products until you start doing novel chemistry.
2). So much trial and error. There were happy go lucky chemists that fell into projects that were smooth as butter, while brilliant chemists would toil 12 hour days to try and something to write up as a thesis. I was neither brilliant nor lucky and took 4 different projects over two years before finally landing on something marginally MS worthy. They need a journal of failed chemistry because only the working stuff gets published. So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions.
3). Suspicious results in journals. I would read about a reaction and someone would put a 75% yield as their result and I could barely get 20. I always thought I was just bad, but a really smart chemist challenged me one day and tried to do it himself and couldn’t do much better. He tried it 30 different ways over the year as he did other stuff. He never could get a good yield. We talked to our advisor and we wanted to challenge the result, but the advisor didn’t want to start trouble. It was past the time I decided to leave with a masters, but made me feel a little better about my lousy abilities. No one could ever possibly doublecheck every result from every publication anyways.
All this said, there are some brilliant and patient scientists out there that drive the field forward. Just a few rough around the edge items I’d love to see change.
> So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions
In a different but related world, clandestine chemists share failures more often than they do their successes, at least in the communities I was a part of a very long time ago.
I'd wager this is because our substrates, reagents and solvents are such a pain in the arse to get compared to an actual lab, that wasting any of them is a no-go if it can be avoided.
Related to that, but we reused solvents and recycled material a lot more than I did doing my B.Sci in Chemistry, for the same reasons!
That's kind of my experience with research, but in physics. Already have three projects under my belt w/ no publishable results. All of them involved much more work than the other grad. students in my lab including building like three different instruments from scratch, but the other students have published. Their projects were much more "safe" than mine and their papers are pretty small, but at least they have papers.
> They need a journal of failed chemistry because only the working stuff gets published.
I think there's theoretical value in this, and many have tried, but the incentives/disincentives for doing so isn't favorable. Here's some reasons why I think it's difficult to motivate people to publish negative results:
1) Negative results, while important in advancing science, don't get you grants.
2) Negative results need to be peer-reviewed -- there are "good" negative results (good protocol, failed result) and "bad" negative results due to bad data collection, wrong conclusions (bad protocol, failed result).
3) Given that it's so much easier to get a negative result than a positive one (as in anything there are only few ways to be right, tons of ways to be wrong), the volume of papers to review is orders of magnitude higher. Reviewers have to really sift to find the needle in the haystack. Between teaching classes, sitting on mindless committees, writing grants, mentoring grad students, etc. academics don't have that kind of time.
4) It would incentivize poor/mediocre labs to publish a lot of negative results to get their pub count up (these are the ones that currently publish unsubstantiated positive results in fly-by-night journals).
5) Bad faith authors may publish fake negative results to throw others off a promising line of inquiry.
(Note: some of these disincentives also apply to positive results in journals today)
The current method I know for exchanging "good" negative results is word-of-mouth, usually during post-conference drinks at the bar. (works for tech too!) I'm not sure if it's possible to arrange incentives in such a way as to make publishing "good" negative results worthwhile.
EDIT: there are exceptions. If the space of solutions is known a priori and bounded (say only n ways to do something), then publishing n results if even all n are failures is worthwhile. This situation doesn't come up all the time (the solution space is often open), but when it does, it's worth publishing all n results.
As someone who spent 4 years working on a PhD (wireless/RF technology) and then quit, your points 2 and 3 ring a lot of bells. I think "journal of failed experiments" is a wonderful idea.
> There were happy go lucky chemists that fell into projects that were smooth as butter
If it makes you feel any better (I 'quit' at the start of my bioinformatics PhD), there's a high chance that their projects went smooth as butter because they were also happy-go-lucky about double-checking their results. See for example that 75% yield paper you mentioned.
I sometimes bake stuff. But had problems with one particular recipe. When changed the proportions I always failed. Tried it over and over. Only to find out one of the baking measurements that's over 20 years old showed the correct measure at 1dl but incorrect on 2 and 2.5 dl. And the recipe only worked when I used the incorrect measurement.
Sharing failures seems like the best way to make progress. I mean we're talking about SCIENCE here. If we don't have a comprehensive list of what does not work, that's just going to make progress so much slower.
In point 3: did you try to contact the authors of the paper you were trying to reproduce?
I don't know organic chemistry, but in my field the authors are often willing to discuss their results, especially if it might mean more citations for them.
As an IT guy, I am wondering why this is still a mostly manual and rather dangerous process. Surely programmable machines can be built to process reagents in a safe and flexible way?
Something that is not obvious from article or posts in this thread, but seems to be taken for granted: how exactly do you know how much of some target molecule you created? The article for example mentions 1g of remdesivir, but that seems like a complicated chemical so how do they tell it apart from something very similar but different? Some kind of GCM or electron microscope?
To what extent can synthesis steps be automated? Do you use a computer to plan how to get to a chemical? Do you use robots to carry out some or all steps?
Your anecdote seems to confirm a number of problems which are ravaging academia at large.
Having gone through a master's myself, I think when we pushed two generations of children into college, we generally lowered the bar - across the board, effectively. And that's related to what's happening in the US today.
> Here are the real numbers for the reactions in Scheme 1: 0.25 x 0.58 x 0.74 x 0.21 x 0.23 = .005 (0.5%)
This reminds me of the problems to scale up EUV lithography which are bottlenecked on producing strong enough EUV light. They put in 20 kW of power to get out 200 W at the target wavelength of 13.5 nm, so light generation itself only has 1% efficiency, and then you need to reflect it at mirrors etc. to focus it (lenses don't work at those wavelength) and that makes only 2% of the light actually reach the waver [2].
It was great, I enjoyed reading so much I forgot how much skill and patience it takes to write that way with such empathy for the reader. Even calling the chemicals names like 15 and 16 is a wonderful abstraction because the point of the article is how difficult the job is, not to teach chemistry and bamboozle people. I hope someone in the Haskell space can do this!
I agree. This had the style of a "Things I won't Work With" column, except that those generally describe experiments done for pure research (or possibly military/rocketry applications).
It's interesting that chemistry for pharmaceutical purposes can involve similarly nasty substances.
The article also does a great job conveying how much of a frustration minuscule yields must be.
I had the same thought, this is wonderfully written. Detailed but accessible for a technically inclined lay audience, fun but not over the top. It's extremely hard to do, so well done and thanks to the author :)
I want to make remark about organic synthesis from the perspective of person who is engineer of chemistry by training as did his fair share of organic synthesis (and eventually moved to computational atomic and molecular physics).
It is one of the oldest and very established fields. Unfortunately practices aren’t great. The preparation formulas are often vogue, imprecise and difficult to reproduce. This comes from the fact that often the sizes and types of glassware are not specified, some informations are omitted (how quickly something is changed not only to what value e.g. heat up to 100 degrees but it does not say over what time) etc. Chemists usually (except some theoretical/computational specialisations) don’t have any training in algorithms or programming.
There are novel developments such as https://www.gla.ac.uk/news/archiveofnews/2018/november/headl...
and references therein. I’m optimistic about them but I expect strong opposition from older faculty. They see synthesis as more than art and think that one has to have “good hand” in order to be a good organic chemist.
I think some generational shift will be necessary in order to change this discipline to more reproducible, strict and reliable. It will come but not that soon :)
It’s a running joke between my readers and me. EVERY SINGLE TIME I have done even the simplest of math (n= more than 20) I’ve screwed it up and been corrected by a reader. I don’t know how I made it out of high school.
Although very interesting, this article isn't a great introduction because a critical part of the picture is missing - the availability of the inputs.
Sticking to simple stuff; mines produce iron at a rate measured in thousand-tonnes per hour with yields of potentially sub-30% compared to volume of earth moved. Ammonia and many acids are presumably measured in tonnes or kilograms produced per day. Low yields make the process-oriented sad, but what matters is absolute ability to produce; not yield.
All that doesn't take anything away from this article; it just makes it hard to interpret what 'royal pain to synthesize' means in practice. The process isn't basic chemistry; but that isn't really saying much.
Low yields make the process-oriented sad, but what matters is absolute ability to produce; not yield
That would be true if reagents, labour and plant equipment were free, but unfortunately they are not. Consequently you have these strange creatures called process chemists who shave steps of the discovery synthesis, increase the yield, and get around difficult reactions. It's really quite magical.
When it comes to bulk chemicals like vinyl acetate (produced at scales of kiloton per day) another consideration is waste. It cuts into profit twice: you lose product and you pay for disposal.
Exaxtly this. Are the inputs available and we can spend just a few tens of billions on building gigafactories to make this process parallel and controlled? Then it’s like making microchips from silicon or gold from ore. Terrible yield but cheap inputs and a scalable process.
If the inputs are expensive or the process can’t scale (to a billion doses in 12 months, say) then that’s worrying and perhaps indicates this isn’t a good candidate vaccine.
Chemistry is absolutely fascinating. One of my long-time goals has been to make a learning chemistry game of some sort. Players building bonds and molecules, solving problems by creating reactions, etc. Orbits and ions and quantum states.
Something truly educational, and of course one of the people I wanted to educate was myself by forcing myself to learn much more than my high-school level of chemistry.
I've gone down this road a few times, each time giving up on the absolutely scale of even the most rudimentary understanding.
This brings me back to orgo lab. A six step synthesis was torture when you were graded by your final yield exactly bc of the compounding nature of small mistakes in each step. Even if you get fairly good yields of 80 to 90% per step, you’d end up with a 53% at best and hope to god that everyone else did equally badly so the curve would save you.
Quote: "Fortunately, there are creatures called "process chemists" – guys who laugh at the discovery synthesis, insult as many of us as possible, and then make it better so that the yields are higher and some of the most dangerous chemical reagents and solvents – ones you really don't want to use on a large scale – are replaced by others. They are generally a bunch of mutants, but they do a great job in "fixing" the synthesis used by the discovery chemists."
This really cracked me up. In my IT world the equivalent for "mutant" would be refactoring, right? I did "mutated" this way a few times in the past to much of the horrors of my boss(es)/manager(s) when they learned the next day.
ML is useful to design the reaction pathways to make these chemicals. If we find safer/better/cheaper ways to make medicines like Remdesivir with deep learning, and publish them, then chemists may have an easier time of it.
If Remdesivir data looks good this month, there will be a rush to produce it, and if there’s only one published way to do that, then the ingredients for that one approach will potentially be hard to find. Thus we can benefit from different approaches which start from different raw materials.
Lots of cool Arxiv papers on this and Graph Neural Nets, Soft actor-critic, or Transformers can be interesting approaches. The transport theory seems like a good way to make a value function. How much time and money does it take to produce a given chemical by a given set of reactions? That’s a gajillion dollar question.
I spent way too much time last year looking at permutation-invariant distance metrics similar to Fused Gromov Wasserstein to invent an Atom Mover Distance, please let me know if you figure that out! DeepChem library is a solid framework, as are Tensorflow and Pytorch...
If anyone’s looking for a way to contribute to the COVID-19 response, open source data/algorithms to design synthesis pathways can be a strong approach. Everyone loves to use Deep Learning to design drugs, but it is valuable to design ways to make drugs, too!
Very funny writing style while being incredibly informative. Read from top to bottom with glee. I had a feeling organic synthesis was difficult but not this difficult.
This makes the biological chemistry so awe-inspiring. Everything is done at about the same body temperature and at the same pressure, just with right catalysts.
I was able to create several small molecule candidates which achieved docking scores of almost -18 but they still need to be assessed for their synthetic feasibility. (Docking scores of leading existing drugs (HIV inhibitors) are around -10 to -11 (the more negative the score the better), Remdesivir drug is around -13 which already entered clinical testing.
I know that binding affinity has been shown not to be the best indicator of efficacy always, but I want to know if it's feasible, if someone can help
Oh the pain of biochemistry! Thanks to the author for making this available to everyone, and reminding these of us who ran screaming from the labs why our decision is not among the ones we might regret. Joking aside, I hope this molecule can be synthesized efficiently, and that it can be preempted from Gilead somehow, as this company has a history of price gouging of the worst kind. They are down there with the oxy makers, the worst of the worst, causing deaths through their pricing policies, and resulting lack of affordable treatment. The ideals of medicine mean nothing to these, and public health should take precedence over the interests of such despicable companies.
I've never learned a bit of Chemistry. I assume there are formulas to determine how substrates and reagents will react with each other? And the process chemists understand these formulas better than most?
Apologies for the assumptions in these question, but are there many reactions in organic chemistry that are completely unknown?
This actually seems pretty fun. I'd love to have a reason to study it and a means to do something with my studies.
> I assume there are formulas to determine how substrates and reagents will react with each other?
Well there are things we've experimentally tested, and things we haven't. Most reactions fall into the latter, and we can only make educated guesses about them.
If we could analytically solve the Schrödinger equation (we can't), we could accurately predict outcomes under perfect reaction conditions.
> are there many reactions in organic chemistry that are completely unknown?
Yes, the vast majority. But bear in mind that we can make educated guesses based on patterns, so we're not completely clueless.
Which country's education system doesn't have any chemistry at all?
Chemical formulae are required study for 11-14 year olds in England, for what it's worth. (Probably starting with words: methane + oxygen → carbon dioxide, and later writing a balanced equation: CH₄ + 2O₂ → CO₂ + 2H₂O.) The reaction presented is obviously much, much more complicated, but the same concept.
"I assume there are formulas to determine how substrates and reagents will react with each other?"
There are rules, yes, of cause. But always the question: how much will react?
And not: will I get the (reaction) product? But: how many (different) reaction products will I get.
This is actually the reason why you need the purification steps after each reaction.
Otherwise you would get an "reaction tree", in the end, byproducts reacting with other byproducts and you would get a, basically infinite amount of different end products.
> remdesivir, possibly the most promising candidate
Is there any evidence of this? It was a highly anticipated drug, but the first studies it was in showed only slight improvement over expected outcomes, far less than was seen with the chloroquine/zinc/antibiotic combo treatment.
I mean I think it's still interesting as a possible drug to add to the cocktail for maximum effectiveness. But let's not oversell it.
"liquid chromatography, is frequently used. On a small scale this is fine, but when kilograms of material are required the process becomes unwieldy."
I did not understand this. liquid chromatography scales up quite well. There are other methods like Electorphoresis, salt precipitations etc., that don't.
> n-BuLi is short for n-butyllithium, which bursts into flame if exposed to oxygen or water.
It looks like the author is overselling some of the dangers here.
While you really don't want to dump n-BuLi into water, you have no reason to either.
The problem child of the class to which n-BuLi belongs is t-BuLi. That will spontaneously ignite in air, whereas n-BuLi will not. There was a very high-profile case I believe at UCLA a few years back in which a student using t-BuLi in the lab caused a fire with it and ended up dying.
Also, I find this article confusing in the way it's written. Take the title, for example. It gives the impression that the author is describing his own efforts to make remdesivir ("we").
What he's really describing is some preps he found in the literature. And with a little too much hyperbole for my taste.
nBuLi is tame compared to tBuLi, I agree. But on large scale the reaction with air can generate enough heat to ignite. (And with humid air it's worse.)
favipiravir is alot cheaper to synthesize and is used as a drop in replacement for remdesivir all over asia...
Good things to have on hand during this covid-19 pandemic (because you can't rely on hospitals to give it to you) are:
1) hydroxychloroquine sulfate taken orally 400 mg per day for a week ($180/kg on alibaba)
2) azithromycin taken orally 500 mg per day for a week ($150/kg on alibaba)
3) Camostat mesilate taking orally 200 mg three times a day for a week [1] ($50/g on alibaba)
4) favipiravir one dose of 1600mg two times on the first day, and then 600mg twice per day after that for a week [2]. ($40/g on alibaba)
5) covid-19 rapid test kits that use blood antibody tests and produce results between 3 to 10 minutes and cost about $1.50 per kit [3] .... although it looks like in the last week or so Alibaba has been blocking searches for these kits for some reason... although the search below does work but you have to look at the suppliers to find the ones that are actually selling it.
all this stuff can be bought on Alibaba and delivered in a week
In research? Usually not much and thats if you can even manage to find a job. But Chemical engineers are usually well paid and can easily get a job out of college. Though maybe that is changing since the oil industry is usually a big part of the job market. And with most of the energy sector currently on the brink of collapse...
If they don't have grants, $0. If they work in a lab for someone who has a grant, $0, but with credit on the papers (that's why there's 35 authors on the paper, 1 person got paid, the rest got name credit in the hopes that they get noticed by a commercial company wanting to monetize this process, so in the future they get their own gig). If they work in a commercial lab, maybe they make a little.
kccqzy|5 years ago
Our body, or really, all biological processes can synthesize incredibly complicated molecules that can take human chemists a huge amount of effort to synthesize. It really is amazing how awesome our body is.
†: My description here is a dumbed down description. For a more precise description see section 2 of Arguments in favour of remdesivir for treating SARS-CoV-2 infections, Wen-Chien Ko et al, https://www.sciencedirect.com/science/article/pii/S092485792...
koboll|5 years ago
> The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus.
Absolute gibberish to someone with limited knowledge of biology.
pfdietz|5 years ago
https://blogs.sciencemag.org/pipeline/archives/2010/10/06/ch...
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002...
ashildr|5 years ago
What I’m curious about is why this huge group attached to the adenosine-like group is needed. It seems to be rather complex for being a shoe to be thrown into cellular gear. Do you have an idea or pointer into the mode of action of this group?
xg15|5 years ago
So, putting the three together, would it be possible to use actual biosynthesis for designed molecules by basically writing your own DNA/RNA and inserting it into a cell?
(Or is this already what's being done?)
heurifk|5 years ago
nbabitskiy|5 years ago
[deleted]
eyegor|5 years ago
Reelin|5 years ago
Disclaimer: I'm terrible at organic chemistry.
As with software engineering, you develop a general sense (I didn't) of what might work and what probably won't. You aren't coming at it blind and reinventing the wheel every time. You learn to recognize patterns in chemical structures and reason about how they will interact under various conditions based on that. You do electron pushing in your head without giving it much thought, similar to a programmer reasoning about object lifetimes or dataflow in an application.
As to -100 C or +5 atm, that's the easy part. You alter environmental conditions when what you're working with is too reactive, or not reactive enough, or you have some other general problem. It's roughly analogous to determining the minimum amount of RAM the machine hosting your production database requires.
perlgeek|5 years ago
That part, at least in theory, is easy to understand.
Chemical reactions are typically of the form:
ingredients + energy -> products + byproducts
If the energy is on the left-hand side, making the environment warm makes the reaction go faster. If energy comes out (so it's on the right-hand side), making it cooler is better. You also need to control the temperature to be in a range where both the ingredients and products can survive.
As for the pressure, if the products and by-products have more total volume than the ingredients, low pressure is good. If it's the other way round, high pressure encourages the reaction.
The more complicated part is that if multiple reactions can happen with the same ingredients, or if the products can do further, unwanted reactions. Then you have to balance out the parameters to encourage just the reaction you want, and to discourage all the others.
Gigablah|5 years ago
https://youtu.be/Y0HfmYBlF8g
xg15|5 years ago
Back then, you had a certain number of mechanical properties in mind as well as well-known "parts" (gears, linkages, etc) that you could predict the properties of very well - and the task was then to assemble them into larger mechanisms that did what you wanted them to do.
Seems to me, the intuition here could be similar - except the number of dimensions in which parts can interact is larger, the "clockworks" are orders of magnitude more complex - and your tools are much more coarse, so mostly, even if you know what you need to build, the building itself can only be done indirectly.
totony|5 years ago
I have a bachelor in chemistry and ochem was one of the most painful classes based on the amount of things you must know by heart for synthesis
applecrazy|5 years ago
heavenlyblue|5 years ago
aerovistae|5 years ago
someguy101010|5 years ago
Metacelsus|5 years ago
For biochemistry check out r/labrats
Vaslo|5 years ago
1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but reality was far different. You don’t think much about side products until you start doing novel chemistry.
2). So much trial and error. There were happy go lucky chemists that fell into projects that were smooth as butter, while brilliant chemists would toil 12 hour days to try and something to write up as a thesis. I was neither brilliant nor lucky and took 4 different projects over two years before finally landing on something marginally MS worthy. They need a journal of failed chemistry because only the working stuff gets published. So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions.
3). Suspicious results in journals. I would read about a reaction and someone would put a 75% yield as their result and I could barely get 20. I always thought I was just bad, but a really smart chemist challenged me one day and tried to do it himself and couldn’t do much better. He tried it 30 different ways over the year as he did other stuff. He never could get a good yield. We talked to our advisor and we wanted to challenge the result, but the advisor didn’t want to start trouble. It was past the time I decided to leave with a masters, but made me feel a little better about my lousy abilities. No one could ever possibly doublecheck every result from every publication anyways.
All this said, there are some brilliant and patient scientists out there that drive the field forward. Just a few rough around the edge items I’d love to see change.
girvo|5 years ago
In a different but related world, clandestine chemists share failures more often than they do their successes, at least in the communities I was a part of a very long time ago.
I'd wager this is because our substrates, reagents and solvents are such a pain in the arse to get compared to an actual lab, that wasting any of them is a no-go if it can be avoided.
Related to that, but we reused solvents and recycled material a lot more than I did doing my B.Sci in Chemistry, for the same reasons!
djaque|5 years ago
wenc|5 years ago
I think there's theoretical value in this, and many have tried, but the incentives/disincentives for doing so isn't favorable. Here's some reasons why I think it's difficult to motivate people to publish negative results:
1) Negative results, while important in advancing science, don't get you grants.
2) Negative results need to be peer-reviewed -- there are "good" negative results (good protocol, failed result) and "bad" negative results due to bad data collection, wrong conclusions (bad protocol, failed result).
3) Given that it's so much easier to get a negative result than a positive one (as in anything there are only few ways to be right, tons of ways to be wrong), the volume of papers to review is orders of magnitude higher. Reviewers have to really sift to find the needle in the haystack. Between teaching classes, sitting on mindless committees, writing grants, mentoring grad students, etc. academics don't have that kind of time.
4) It would incentivize poor/mediocre labs to publish a lot of negative results to get their pub count up (these are the ones that currently publish unsubstantiated positive results in fly-by-night journals).
5) Bad faith authors may publish fake negative results to throw others off a promising line of inquiry.
(Note: some of these disincentives also apply to positive results in journals today)
The current method I know for exchanging "good" negative results is word-of-mouth, usually during post-conference drinks at the bar. (works for tech too!) I'm not sure if it's possible to arrange incentives in such a way as to make publishing "good" negative results worthwhile.
EDIT: there are exceptions. If the space of solutions is known a priori and bounded (say only n ways to do something), then publishing n results if even all n are failures is worthwhile. This situation doesn't come up all the time (the solution space is often open), but when it does, it's worth publishing all n results.
avian|5 years ago
nython|5 years ago
If it makes you feel any better (I 'quit' at the start of my bioinformatics PhD), there's a high chance that their projects went smooth as butter because they were also happy-go-lucky about double-checking their results. See for example that 75% yield paper you mentioned.
z3t4|5 years ago
fouc|5 years ago
eru|5 years ago
I got similar stories about how to (not..) grow mammalian cells in vats.
wesleywt|5 years ago
dguest|5 years ago
I don't know organic chemistry, but in my field the authors are often willing to discuss their results, especially if it might mean more citations for them.
lazyjones|5 years ago
foobarian|5 years ago
wuschel|5 years ago
rwmj|5 years ago
godzillabrennus|5 years ago
twomoretime|5 years ago
Having gone through a master's myself, I think when we pushed two generations of children into college, we generally lowered the bar - across the board, effectively. And that's related to what's happening in the US today.
est31|5 years ago
This reminds me of the problems to scale up EUV lithography which are bottlenecked on producing strong enough EUV light. They put in 20 kW of power to get out 200 W at the target wavelength of 13.5 nm, so light generation itself only has 1% efficiency, and then you need to reflect it at mirrors etc. to focus it (lenses don't work at those wavelength) and that makes only 2% of the light actually reach the waver [2].
[1]: https://www.laserfocusworld.com/blogs/article/16569161/the-s...
[2]: https://en.wikipedia.org/wiki/Extreme_ultraviolet_lithograph...
ebg13|5 years ago
Josh_Bloom|5 years ago
samcheng|5 years ago
https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th...
It seems there are multiple chemist-author hybrids out there!
quickthrower2|5 years ago
sq_|5 years ago
microtherion|5 years ago
It's interesting that chemistry for pharmaceutical purposes can involve similarly nasty substances.
The article also does a great job conveying how much of a frustration minuscule yields must be.
IanCal|5 years ago
tikej|5 years ago
It is one of the oldest and very established fields. Unfortunately practices aren’t great. The preparation formulas are often vogue, imprecise and difficult to reproduce. This comes from the fact that often the sizes and types of glassware are not specified, some informations are omitted (how quickly something is changed not only to what value e.g. heat up to 100 degrees but it does not say over what time) etc. Chemists usually (except some theoretical/computational specialisations) don’t have any training in algorithms or programming.
There are novel developments such as https://www.gla.ac.uk/news/archiveofnews/2018/november/headl... and references therein. I’m optimistic about them but I expect strong opposition from older faculty. They see synthesis as more than art and think that one has to have “good hand” in order to be a good organic chemist.
I think some generational shift will be necessary in order to change this discipline to more reproducible, strict and reliable. It will come but not that soon :)
franciscop|5 years ago
Josh_Bloom|5 years ago
unknown|5 years ago
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mettamage|5 years ago
I like HN in general, but this particular article gave me the same feeling that I had when I first discovered HN a couple of years ago.
roenxi|5 years ago
Sticking to simple stuff; mines produce iron at a rate measured in thousand-tonnes per hour with yields of potentially sub-30% compared to volume of earth moved. Ammonia and many acids are presumably measured in tonnes or kilograms produced per day. Low yields make the process-oriented sad, but what matters is absolute ability to produce; not yield.
All that doesn't take anything away from this article; it just makes it hard to interpret what 'royal pain to synthesize' means in practice. The process isn't basic chemistry; but that isn't really saying much.
HarryHirsch|5 years ago
That would be true if reagents, labour and plant equipment were free, but unfortunately they are not. Consequently you have these strange creatures called process chemists who shave steps of the discovery synthesis, increase the yield, and get around difficult reactions. It's really quite magical.
When it comes to bulk chemicals like vinyl acetate (produced at scales of kiloton per day) another consideration is waste. It cuts into profit twice: you lose product and you pay for disposal.
alkonaut|5 years ago
If the inputs are expensive or the process can’t scale (to a billion doses in 12 months, say) then that’s worrying and perhaps indicates this isn’t a good candidate vaccine.
endorphone|5 years ago
Something truly educational, and of course one of the people I wanted to educate was myself by forcing myself to learn much more than my high-school level of chemistry.
I've gone down this road a few times, each time giving up on the absolutely scale of even the most rudimentary understanding.
abhisuri97|5 years ago
unnouinceput|5 years ago
This really cracked me up. In my IT world the equivalent for "mutant" would be refactoring, right? I did "mutated" this way a few times in the past to much of the horrors of my boss(es)/manager(s) when they learned the next day.
bionhoward|5 years ago
If Remdesivir data looks good this month, there will be a rush to produce it, and if there’s only one published way to do that, then the ingredients for that one approach will potentially be hard to find. Thus we can benefit from different approaches which start from different raw materials.
Lots of cool Arxiv papers on this and Graph Neural Nets, Soft actor-critic, or Transformers can be interesting approaches. The transport theory seems like a good way to make a value function. How much time and money does it take to produce a given chemical by a given set of reactions? That’s a gajillion dollar question.
I spent way too much time last year looking at permutation-invariant distance metrics similar to Fused Gromov Wasserstein to invent an Atom Mover Distance, please let me know if you figure that out! DeepChem library is a solid framework, as are Tensorflow and Pytorch...
If anyone’s looking for a way to contribute to the COVID-19 response, open source data/algorithms to design synthesis pathways can be a strong approach. Everyone loves to use Deep Learning to design drugs, but it is valuable to design ways to make drugs, too!
gorgoiler|5 years ago
Missed a trick not titling it:
“(1OO)OMG we made one gram...” :)
failuser|5 years ago
manav|5 years ago
ehsankia|5 years ago
saadalem|5 years ago
I know that binding affinity has been shown not to be the best indicator of efficacy always, but I want to know if it's feasible, if someone can help
person_of_color|5 years ago
jluxenberg|5 years ago
VSerge|5 years ago
ngngngng|5 years ago
Apologies for the assumptions in these question, but are there many reactions in organic chemistry that are completely unknown?
This actually seems pretty fun. I'd love to have a reason to study it and a means to do something with my studies.
Reelin|5 years ago
Well there are things we've experimentally tested, and things we haven't. Most reactions fall into the latter, and we can only make educated guesses about them.
If we could analytically solve the Schrödinger equation (we can't), we could accurately predict outcomes under perfect reaction conditions.
> are there many reactions in organic chemistry that are completely unknown?
Yes, the vast majority. But bear in mind that we can make educated guesses based on patterns, so we're not completely clueless.
Symbiote|5 years ago
Chemical formulae are required study for 11-14 year olds in England, for what it's worth. (Probably starting with words: methane + oxygen → carbon dioxide, and later writing a balanced equation: CH₄ + 2O₂ → CO₂ + 2H₂O.) The reaction presented is obviously much, much more complicated, but the same concept.
Edit: catalysts are covered too, although I don't know if the notation of putting them above the → is introduced at this age. https://www.bbc.co.uk/bitesize/guides/zqd2mp3/revision/6
joyj2nd|5 years ago
There are rules, yes, of cause. But always the question: how much will react? And not: will I get the (reaction) product? But: how many (different) reaction products will I get. This is actually the reason why you need the purification steps after each reaction. Otherwise you would get an "reaction tree", in the end, byproducts reacting with other byproducts and you would get a, basically infinite amount of different end products.
unknown|5 years ago
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garmaine|5 years ago
Is there any evidence of this? It was a highly anticipated drug, but the first studies it was in showed only slight improvement over expected outcomes, far less than was seen with the chloroquine/zinc/antibiotic combo treatment.
I mean I think it's still interesting as a possible drug to add to the cocktail for maximum effectiveness. But let's not oversell it.
joyj2nd|5 years ago
I did not understand this. liquid chromatography scales up quite well. There are other methods like Electorphoresis, salt precipitations etc., that don't.
Metacelsus|5 years ago
Not compared to recrystallization or distillation. Try running a column on 10kg scale and get back to me.
(I worked in an o-chem lab for 2 years in undergrad, and the biggest we could do was ~20 grams at once)
aazaa|5 years ago
It looks like the author is overselling some of the dangers here.
While you really don't want to dump n-BuLi into water, you have no reason to either.
The problem child of the class to which n-BuLi belongs is t-BuLi. That will spontaneously ignite in air, whereas n-BuLi will not. There was a very high-profile case I believe at UCLA a few years back in which a student using t-BuLi in the lab caused a fire with it and ended up dying.
https://cen.acs.org/articles/87/i31/Learning-UCLA.html
Also, I find this article confusing in the way it's written. Take the title, for example. It gives the impression that the author is describing his own efforts to make remdesivir ("we").
What he's really describing is some preps he found in the literature. And with a little too much hyperbole for my taste.
Metacelsus|5 years ago
Scoundreller|5 years ago
You're in luck, the first dose is 200mg, and then 100 mg daily after that.
Unfortunately, it's also IV, so you have a number of extra steps after synthesis to ensure sterility.
aledalgrande|5 years ago
jijji|5 years ago
Good things to have on hand during this covid-19 pandemic (because you can't rely on hospitals to give it to you) are:
1) hydroxychloroquine sulfate taken orally 400 mg per day for a week ($180/kg on alibaba)
2) azithromycin taken orally 500 mg per day for a week ($150/kg on alibaba)
3) Camostat mesilate taking orally 200 mg three times a day for a week [1] ($50/g on alibaba)
4) favipiravir one dose of 1600mg two times on the first day, and then 600mg twice per day after that for a week [2]. ($40/g on alibaba)
5) covid-19 rapid test kits that use blood antibody tests and produce results between 3 to 10 minutes and cost about $1.50 per kit [3] .... although it looks like in the last week or so Alibaba has been blocking searches for these kits for some reason... although the search below does work but you have to look at the suppliers to find the ones that are actually selling it.
all this stuff can be bought on Alibaba and delivered in a week
[1] https://clinicaltrials.gov/ct2/show/NCT04321096
[2] https://www.medicalnewstoday.com/articles/anti-flu-drug-effe...
[3] https://m.alibaba.com/products/covid-19_rapid_test_kit.html
autonoshitbox|5 years ago
Stop suggesting people buy dangerous drugs from Alibaba. This should be bannable.
fg6hr|5 years ago
mardifoufs|5 years ago
barkingcat|5 years ago
unknown|5 years ago
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Josh_Bloom|5 years ago
Josh_Bloom|5 years ago
nik_0_0|5 years ago
Glosster|5 years ago
franciskim|5 years ago
quickthrower2|5 years ago