They're referring to the structure of the protein when a drug is bound, that's what's novel. Novel as in, you can't think of it as "just" interpolation between known structures of evolutionarily related proteins.
That said I'm not sure that's entirely fair, since Alphafold does, as far as I know, work for predicting structures that are far away from structures that have previously been measured.
You're quite wrong about small molecule drug structures. Historically that has been the case but these days many lead structures are made by combinatorial chemistry and are not derived from natural products.
But even drugs made by combinatorial chemistry still generally end up being analogues of natural products even if they aren't derived from them. As Leslie Orgel said "Evolution is cleverer than you are"; chemists are unlikely to discover a mechanism of action that millions of years of evolution hasn't already found.
I... Don't think that's right? Although I would appreciate being corrected with some good sources on this. It's a fast moving field and combinatorial chemistry is still new enough that many recently published structures wouldn't have used it.
I'm well aware of the impact of natural products and particularly plant secondary metabolites in drug discovery. I'm also aware of combinatorial synthesis occasionally hitting structures that are close to natural products.
But from first principles, why would you need to limit yourself to that subset of molecular space?
Obviously, your structure will need to look vaguely biochemical to be compatible with the bodies chemical environment, but natural products are limited to biochemically feasible syntheses, and are therefore dominated by structures derived from natural amino acids and similar basic biochemical building blocks.
For a concrete example off the top of my head, I'm not aware of any natural diazepines - the structure looks "organic" but biochemistry doesn't often make 7-rings, and those were made long before combinatorial chemistry. Might be wrong on this one, since there's so much out there, but I think it holds.
Perhaps we are using "structure" in different senses. Yes, it is possible to generate a molecule with a chemical structure unlike any biological molecule and have it bind to a protein, but it can only do so if its 3D structure is analogous to what naturally binds there. Natural products are a source of drugs because evolution has already done this work for us.
Yes, the chemical structures can look very different when drawn in the 2D manner, but that's why 2D structures aren't very useful for understanding binding, much as primary sequences of proteins aren't that useful. Morphine and fentanyl bind to μ-opioid receptors, just like what naturally binds there (endorphins and enkephalin). But if they are binding to the same receptor, they have to have similar structures in the biologically meaningful 3D sense (at least where they bind).
It appears that you were merely saying that ligands must adopt a 3D conformation that's complementary to the receptor. Sure. That's the entire premise of molecular docking software.
But there can be very dissimilar ligands (like morphine and fentanyl) binding the same receptors. A major goal of drug discovery is to find such novel binders, not to regurgitate known ones.
That said I'm not sure that's entirely fair, since Alphafold does, as far as I know, work for predicting structures that are far away from structures that have previously been measured.
You're quite wrong about small molecule drug structures. Historically that has been the case but these days many lead structures are made by combinatorial chemistry and are not derived from natural products.