Can someone explain whether design of protein binders is an important rate-limiting step in drug creation (of which antivenom is a very small market)? Or AI-driven drug discovery in general? It feels like something that will definitely help the drug market but is nowhere near the rate-limiting step, but that's from my own researcher as someone without a background in it.
My understanding is that FDA trials (specifically phase 2 + 3) are the death valley for most drugs and finding a biomarker is something mostly done through a mix of gene bank scraping + looking at old biomarker databanks. The majority of the cost and time is in failed drugs that do not pass FDA trials (which average 6-7 years end-to-end).
Note: I am asking this in earnest. I am not trying to ask a leading question and saying it is not important at all.
Have a comment below on this, but generally things don't work out in the clinic because we didn't understand the biology adequately, and not because we didn't have a molecule.
A better binder only helps if you know what to bind to and that if you bind to it, you'll have the desired effect.
This is why the industry has crowded around a very limited set of "validated" targets. It's because we know if we do something with them, they will work. Obviously we're likely missing a lot of great ideas though.
AI might help find some of those ideas, but we won't know until someone tests them in a human. Essentially, without more extremely expensive and difficult data to acquire, it's not likely to be that much better at picking winners.
I'm in the sector and I believe strongly in AI helping (I've bet my entire career on it). It will get there eventually, but it will take much longer than people seem to think at the big labs.
On crowding in big pharma: https://www.lek.com/insights/life-sciences-pharma/biopharma-...
Parent comment reached out asking for examples so thought I'd post my answer here:
We thought clearing amyloid beta plaques would slow alzheimer’s disease. We now have antibodies that do clear the plaques quite effectively, however they barely show any clinical benefit. Some trials failed entirely, others cleared a statistical bar that clinicians agree would be hard to detect by someone just living with the person. Essentially all patients given this drug still decline at more or less the same rate they declined before getting the drug. Definitely not the “we took away the cause of the disease, so at least they’ll stay about the same as they are today” effect we were hoping for.
To find this out, many trials costing (hard to get the specific number) but hundreds of millions of dollars had to be run. And this was easily the consensus target for solving Alzheimer’s.
If AI magically comes up with a new idea (Eliminate Protein X and Alzheimer’s will stop in its tracks), it will take us that long and that much money to know if it was right.
And before that we’ll have to run a huge number of lab experiments, likely involving developing new model systems (engineered mice usually, but not always) to test the concept before a human gets the drug.
So even assuming an AI model today is a “Genius” level talent, and that the target we need to go after is really already in some pre-existing paper or dataset, it will take a huge amount of investment to know.
And again, likely we need more data about how Alzheimer's works, because our best ideas haven’t worked the way we expected. Maybe AI can help us design ways to get that data, or ideas for what to gather. But it’s not going to magically come up with an answer where we simply do not know.
There’s a huge cardiology trial using Lp(a) as a target that just failed because it turns out that lowering cholesterol using the drug doesn’t actually reduce cardiac events. This was the most genetically validated open target in cardiology, and it turns out to not work how we thought. Hundreds of millions of dollars lost. (https://www.cnbc.com/2026/09/08/novartis-cholesterol-setback...)
Take another unrelated example: If AI told me, “I’ve done a bunch of geology, and I know there’s a huge vat of oil under the ground over there”. You’re gonna need to drill to find out. And if you give the AI all the information you have about geology and it says, “Maybe there’s oil under the ground over there, but I can’t be sure unless you take these rock samples”. Then someone needs to go out and get the rock samples, grind them up, stick it in a machine, get the data.
All those things take time and money. Ideas are cheap, measurements cost time and money. In drug discovery, we’re often against the frontier of what we know. Past the frontier you need new data. In computational fields (coding, video games, maybe in some ways mathematics) you can convert compute into data. In biology and the physical world, you have to do measurements. Compute can’t help you at the edge of data in the physical world.
My understanding is it is not - this is something we have models for, and there was a flurry of machine learning based drug discovery companies about 8-10 years ago. But they ran into the testing bottleneck real fast because they would spit out thousands of candidates for binders and so on that all needed to be tested in vitro before they could even start the real drug dev circuit. Furthermore the drugs need to be manufacturable and that's not a trivial problem.
It's nice to (as the blog post suggests) give the opportunity to non medical experts, say in this case a snake/venom research center, to pursue a problem and produce some realistic candidates that they could pay to test. I do think it's good to democratize what parts of the process can be, but it's more of a resource prioritization problem than a molecular design one.
While Clinical Trials are the most expensive step and have a 90% failure rate, it is not the *source* of the failures, it's just where failures are revealed.
Much of whether or not a candidate drug will succeed was determined all the way back in the design/discovery stage. If we can design better drugs, then we would enjoy a higher probability of success in the later clinical trials.
The single biggest improvement to pharma drug development would be from increasing the probability of success in clinical trials.
Is it fair to say the source of the failures is we simply do not understand the complex relationship between the drug design (chemistry, cell therapy, etc.) and the biology (the complete system of the living thing). If we could understand that relationship, we could design better drugs? I know this is very hand-wavy. Probably so much so as to not be a useful thing to say, but I'm just trying to understand.
Not necessarily. It is often due to a lack of choices (in lead candidates).
Correct. The on-target effects of antivenin can be well-modeled along with a known subset of off-target effects, but the latter is far too complex and unknown to model completely.
Trials are the acceptable middle ground that uses animal and human models to explore those unknowns.
Some trials fail because we didn't have a "better" drug for a given target, many fail because we don't know the right biology. Biology and knowing precisely how to modulate the right thing is more gating than "design a better compound".
Better for what is the question and while sometimes the answer is "solubility, metabolism, off target toxicity", more often it's "you misunderstood something about the biology of this disease".
Maybe you needed more potency than your assays said you needed.
Maybe you missed something else the target does.
Maybe you had the right effect on the target but the body found a way to compensate (in an undesirable way).
Maybe the target looks like it matters in all sorts of model systems, but in real life it doesn't matter at all!
Many such cases. AI might marginally help in these scenarios, but doesn't look like it will eliminate the problem. AI can't help us with what we fundamentally don't know and have zero data for, or for which data is extremely hard to get.
Protein binders (as in, small proteins like the one in the article that themselves bind other proteins) aren't a rate-limiting step, but also are fairly restricted in their applications as therapeutics. Designing small-molecule ligands is much more challenging, and AI/ML design tools for small molecules are much less effective for a number of reasons, including 1) existing training data are sparse the search space for small molecules is arguably much larger and more complex than for proteins 2) the evolutionary data that powers protein structure prediction and design don't exist for small molecules. So it is still non-trivial to design a small-molecule binder for a protein.
It's true that clinical trials are a big cost center for drug development, but there is an argument for mitigating failure here earlier in the process through better technology development. Some of this will come from AI and some of it from better experimental methods for probing biology. One of my favorite efforts in this area is OpenADMET, which combines ML and experimental methods for addressing tox-related issues in drug discovery, which are common causes for failure in the later (more expensive) clinical trial stages:
https://www.nature.com/articles/s41467-026-73410-8 https://openadmet.org
Thank you! Also, OpenADMET is sick
The impression I have, which admittedly is purely as a layman reading articles, is that by far the rate-limiting factor in all drug creation is the cost of doing clinical trials in humans.
Your impression is correct. Clinical trials are the rate limiting step and the primary source of cost and risk.
my general question with any drug isn't its effectiveness. It is what are the side effects? Unless somehow AI is solving this without clinical trials, there isn't much of note here
There would be less failures if problematic therapies were filtered out before the clinical stage.
Both "yes" and "no". AI has been doing great in protein structure prediction.
It's a task that is well suited for the current generation of AIs, (most) proteins consist of a constrained "alphabet" of components, and the alphabet then forms recognizable shapes ("motifs"). So working backwards and generating a protein that binds with another protein is the logical next step.
The problem is in the efficacy. Monoclonal antibodies work surprisingly poorly as antivenoms. They are too specific, and real venom is a mix of multiple kinds of proteins with a lot of variation. Which makes sense, as venoms are under high selective pressure, so there's going to be a lot of genetic variability within a single species (never mind _across_ species).
Snake antivenoms are a major underserved area with a decent amount of research. But so far the century-old method of producing antivenoms (injecting horses and then collecting their blood plasma) is the best one.