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.

https://en.wikipedia.org/wiki/Functional_analog_(chemistry) explains the difference between structural and functional analogs: fentanyl is quite dissimilar from morphine, but binds the same targets.

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).

You originally wrote:

> very, very, few drugs are "novel" as opposed to being analogues of something naturally in the body

But "analog" means "structural analog" in this context (see https://en.wikipedia.org/wiki/Structural_analog ), which is why people disagreed with you, presumably.

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.