Not a bottleneck so much as a numbers game. Difficult diseases require many shots on goal to maximise the chance of a successful program. That means trying to go after as many biological targets as there are rationales for, and a variety of different approaches (or chemical series) for each target. Success may even require knocking out two targets in a drug combination approach. You don’t absolutely need protein structures of a target to have a successful drug-design program but using them as a template for molecular design (Structure-Based Drug Design) is a successful and well established approach and and can give rise to alternative chemical series to non-structure based methods. X-ray crystal derived protein structures are the usual way in but if you are unable to generate X-Ray structures, which is still true for many targets, AlphaFold structures can in principle provide the starting point for a program. They can also help generate experimental structures in cases where the X-ray data is difficult to interpret.
I agree with you on both counts. So, I concede, saving millions in research costs may be small beer. But I don’t see that invalidates the argument in my previous comment, which is about getting good drugs discovered as fast as is feasible. Achieving this will still have significant economic and humanitarian benefit even if they are no cheaper to develop. There are worthwhile drugs we have today that we wouldn’t have without Structure-Based Design.
The solving of the protein folding problem will also help us to design artificial enzymes and molecular machines. That won‘t be small potatoes either IMO.
It’s unclear to me why we should expect protein-structure prediction to be the bottleneck for finding an Alzheimer cure.
Not a bottleneck so much as a numbers game. Difficult diseases require many shots on goal to maximise the chance of a successful program. That means trying to go after as many biological targets as there are rationales for, and a variety of different approaches (or chemical series) for each target. Success may even require knocking out two targets in a drug combination approach. You don’t absolutely need protein structures of a target to have a successful drug-design program but using them as a template for molecular design (Structure-Based Drug Design) is a successful and well established approach and and can give rise to alternative chemical series to non-structure based methods. X-ray crystal derived protein structures are the usual way in but if you are unable to generate X-Ray structures, which is still true for many targets, AlphaFold structures can in principle provide the starting point for a program. They can also help generate experimental structures in cases where the X-ray data is difficult to interpret.
Most of the money spent in developing drugs is not about finding targets but about running clinical studies to validate targets.
The time when structure-based drug design became possible did not coincide with drug development getting cheaper.
I agree with you on both counts. So, I concede, saving millions in research costs may be small beer. But I don’t see that invalidates the argument in my previous comment, which is about getting good drugs discovered as fast as is feasible. Achieving this will still have significant economic and humanitarian benefit even if they are no cheaper to develop. There are worthwhile drugs we have today that we wouldn’t have without Structure-Based Design.
The solving of the protein folding problem will also help us to design artificial enzymes and molecular machines. That won‘t be small potatoes either IMO.