D.E.Shaw was my former employer. I wish him success.
The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
11–20 of 51 posts
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#12Yup. And judging by their team and strategy they are likely using a highly empirical ligand discovery platform (ie DEL) and using the (admittedly best in class) MD for guiding med chem. Taking the hard problem of drug discovery and then saying you are going to do rational design (a road riddled with dead bodies) on dynamic alloseteric sites of challenging targets is a lofty goal to put it mildly..
Dead bodies as in patients harmed or failed attempts?
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#13It really remains to be seen whether these approaches will make any difference in efficacy or cost of pharmaceuticals. Blindly thinking that having better simulations of proteins and drugs is going to solve any of the hard problems has led to a great deal of waste.
A great deal of waste? 25 years ago we thought that genomics would boost drug discovery and development. It didn't pan out quite like that but thanks to the Human Genome Project costs for sequencing have dropped to almost nothing, and we have learned a great deal about protein evolution. Talk about waste!
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#14Earlier quoted context omitted.
I’m not sure why you consider it a great deal of waste. Building better models that simulate a human biological process must have some sort of payoff? It increases human knowledge, and should provide a foundation on which others can build.
A waste for society? No. A waste for the people doing it who are never going to be appropriately compensated for the value of their failure to society? Yes. The churn that arises as a consequence of the fact that we don't know how to reward failure (or even merely punish it less) is the real waste.
???? I assure you, Mark Murcko (and others at Relay) are paid competitively to similar people in pharma.
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#15It really remains to be seen whether these approaches will make any difference in efficacy or cost of pharmaceuticals. Blindly thinking that having better simulations of proteins and drugs is going to solve any of the hard problems has led to a great deal of waste.
Most of the cost is regulatory. But there is a meaningful difference between a world in which it costs $1M to screen and a world in which it costs $100k to screen. In the latter world, startups become viable with intent to find a drug candidate, rather than only being viable if they already have one. That's a big important difference, and one that was only otherwise going to be solved by everyone transitioning from s…
The real cost occurs in Phase 2 clinical trials, where 70 % of promising-looking compounds turn out to be no better than placebo. The body is a complex system with a huge number of enzymes and feedback circuits, this outcome isn't much of a surprise then.
You can't blame the FDA. But thanks to Trump's "right-to-try" phase 2 will be a smaller hurdle now. Good luck, let's see how costs develop.
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#16Earlier quoted context omitted.
I’m not sure why you consider it a great deal of waste. Building better models that simulate a human biological process must have some sort of payoff? It increases human knowledge, and should provide a foundation on which others can build.
A waste for society? No. A waste for the people doing it who are never going to be appropriately compensated for the value of their failure to society? Yes. The churn that arises as a consequence of the fact that we don't know how to reward failure (or even merely punish it less) is the real waste.
> A waste for the people doing it who are never going to be appropriately compensated for the value of their failure to society? Yes.
Judging by their profiles, I don't think they care if they end up being a failure with this Venture.
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#17It really remains to be seen whether these approaches will make any difference in efficacy or cost of pharmaceuticals. Blindly thinking that having better simulations of proteins and drugs is going to solve any of the hard problems has led to a great deal of waste.
I’m not sure why you consider it a great deal of waste. Building better models that simulate a human biological process must have some sort of payoff? It increases human knowledge, and should provide a foundation on which others can build.
> Building better models that simulate a human biological process must have some sort of payoff? It increases human knowledge, and should provide a foundation on which others can build.
That really is still not clear for the models described in the article. In reality, these models are rehashes of what Murcko was having people do 25 years ago. Big articles were written about Vertex applying Free Energy Perturbation with pictures of Murcko accompanied by David Pearlman and Govinda Bhisetti. A book was written about these efforts, The Billion-Dollar Molecule, and more recently a sequel which partially describes how Vertex's efforts using these methods failed (The Antidote).
Obviously, computational power has improved by orders of magnitude since 1989. So have our parameters for modeling proteins and small molecules. But it really is still not clear that MD or FEP really provide any useful insights into proteins that cannot be obtained more simply via NMR-based screens and linear regression. In fact, I recently saw a talk by Relay's VP of Computation where he described using Free Wilson Analysis at Relay[1] for their drug discovery, which is a linear regression method from 1964...
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#18It really remains to be seen whether these approaches will make any difference in efficacy or cost of pharmaceuticals. Blindly thinking that having better simulations of proteins and drugs is going to solve any of the hard problems has led to a great deal of waste.
I'm not going to cry for Shaw if he wastes his money. He has mountains of it...
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#19Yup. And judging by their team and strategy they are likely using a highly empirical ligand discovery platform (ie DEL) and using the (admittedly best in class) MD for guiding med chem. Taking the hard problem of drug discovery and then saying you are going to do rational design (a road riddled with dead bodies) on dynamic alloseteric sites of challenging targets is a lofty goal to put it mildly..
Dead bodies as in patients harmed or failed attempts?
Failed attempts. The regulatory framework in the US and Europe is still pretty good at protecting patients.
Re: The Quant King, the Drug Hunter, and the Quest to Unlock New Cures
#20I see you there, Ubuntu desktop :)
Interesting he's using a mbp box as a monitor stand.
On to a more serious note: is this kind of computing work sped up with GPUs?