We Made One Gram Of Remdesivir • Hacker News Board

Re: We Made One Gram Of Remdesivir

#111

Post by SanderSantema » Sun, Apr 05, 2020, 11:39 AM UTC

xg15 wrote: post #102

kccqzy wrote: post #22

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 i…

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 basical…

I'm no expert, but I believe it's indeed what they're already doing: https://en.wikipedia.org/wiki/Genetically_modified_bacteria#...

But if I could make a guess I'd say that it in theory it might be relatively straightforward or easy to do but it's probably a lot harder in practice. That's often the case anyways.

Re: We Made One Gram Of Remdesivir

#112

Post by lazyjones » Sun, Apr 05, 2020, 11:39 AM UTC

EL_Loco wrote: post #107

lazyjones wrote: post #103

Earlier quoted context omitted.

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?

There are machines that do this. Prety expensive though. Maybe too expensive for a uni's department where there won't be enough work to justify the machine's price?

Not sure how flexible this one is, but it looks cheap enough for a small department to make their own sildenafil: https://science.sciencemag.org/content/363/6423/eaav2211.ful...

The yields are quite bad though AFAICT.

Re: We Made One Gram Of Remdesivir

#113

Post by joyj2nd » Sun, Apr 05, 2020, 11:40 AM UTC

xg15 wrote: post #102

kccqzy wrote: post #22

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 i…

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 basical…

Short answer: Yes

Long answer: No. It would be an incredibly complex undertaking.

Re: We Made One Gram Of Remdesivir

#114

Post by joyj2nd » Sun, Apr 05, 2020, 11:43 AM UTC

"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.

Re: We Made One Gram Of Remdesivir

#115

Post by davikr » Sun, Apr 05, 2020, 11:45 AM UTC

someguy101010 wrote: post #6

aerovistae wrote: post #2

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.

Is there a Hacker News equivalent for Medicine? Maybe r/medicine is really the only similar place..?

Re: We Made One Gram Of Remdesivir

#116

Post by bionhoward » Sun, Apr 05, 2020, 11:45 AM UTC

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!

Re: We Made One Gram Of Remdesivir

#117

Post by joyj2nd » Sun, Apr 05, 2020, 11:47 AM UTC

ngngngng wrote: post #36

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…

"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.

Re: We Made One Gram Of Remdesivir

#118

Post by tikej » Sun, Apr 05, 2020, 11:50 AM UTC

lazyjones wrote: post #103

Vaslo wrote: post #34

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 rea…

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?

People are working on it: https://www.gla.ac.uk/news/archiveofnews/2018/november/headl...

I am chemical engineer and in my studies there was no programming and algorithm training at all (we did tiny bit of Scilab to solve some systems of equations but that’s all!).

Chemists in general (beyond theoretical and some open-minded exeptions) don’t program and don’t want to program. Synthetic/organic chemist still perceive synthesis as form of “art” ;) Therefore it would require huge shift in the mentality.

It is going to happen but not easily and and later than it could for social reasons :(

Re: We Made One Gram Of Remdesivir

#119

Post by cushychicken » Sun, Apr 05, 2020, 11:51 AM UTC

djaque wrote: post #79

joshvm wrote: post #64

Earlier quoted context omitted.

Don't worry. Instrumentation is a pain for publishing because often it creeps into engineering territory. I spent a year of my PhD trying to get something to work, it didn't and I ended up building an entirely new instrument in the third year. That's how it goes. I know people who came out of their PhDs with five papers (in the UK that's a big deal), but they're in fields where its relatively easy to publish and/or g…

Thanks, that's good to hear. Fortunately I do have two papers in the works right now, one of them from an instrument I made and another from some simulation work. The engineering really is the crux of the problem. I personally find it very interesting and I feel like an oddity in my department for that. Most other physicists kind of look down on the "e-word" to the point that my advisors made me change references to…

What field would you go into if you were interested in making instruments for scientific research? Would that be engineering physics?

Re: We Made One Gram Of Remdesivir

#120

Post by tikej » Sun, Apr 05, 2020, 12:00 PM UTC

CamperBob2 wrote: post #101

rwmj wrote: post #86

Earlier quoted context omitted.

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?

I asked this question once. I couldn't figure out why there's no SPICE for chemistry (SPICE being any of several accurate, refined, and well-understood simulation programs for EE work). You know the whole deal with the three-body problem? How closed-form solutions become intractable in a hurry once you go past two or three mutually-influential orbiting bodies? As it was explained to me, that's why there's no SPICE fo…

(Quantum) Many body problem is indeed at the very heart of chemistry. If it was solved creation of new materials and chemicals would be less of trial and error.

In principle it comes down to the fact that problem space explodes tensorially with number of electrons e.g. in principle you need grid size of 3N dimensions per every electron so for helium a^6 where a is number of points in the grid (and you probably need at least thousands of tens of thousands to accurately solve differential equations). This can’t be done in practice so other methods (expansion of problem in basis usually) are used.

Unfortunately solving Schrödinger precisely requires incredible amounts of both computing power and theoretical expertise. Qualitative results are up there for most systems thanks to developments in theoretical chemistry but it is still quite manual process that requires expert computational scientist to make sure results are reliable.